Compositions and methods for inhibition of the JAK pathway

ABSTRACT

The invention encompasses compounds having formula I and the compositions and methods using these compounds in the treatment of conditions in which modulation of the JAK pathway or inhibition of JAK kinases, particularly JAK3, are therapeutically useful.

RELATED APPLICATIONS

This application is a continuation of U.S. application Ser. No.12/053,382, filed Mar. 21, 2008, which in turn claims the benefit ofU.S. Provisional Application Ser. No. 60/896,823, filed Mar. 23, 2007,and U.S. Provisional Application Ser. No. 60/910,749, filed Apr. 9,2007, each of which is incorporated herein by reference.

INTRODUCTION

A. Field

The present invention relates to compounds, prodrugs, and methods ofusing these compounds and prodrugs thereof in the treatment ofconditions in which modulation of the JAK pathway or inhibition of JAKkinases, particularly JAK3, are therapeutically useful.

B. Background

Protein kinases constitute a large family of structurally relatedenzymes that are responsible for the control of a variety of signaltransduction processes within cells (see, e.g., Hardie and Hanks, TheProtein Kinase Facts Book, I and II, Academic Press, San Diego, Calif.,1995). Protein kinases are thought to have evolved from a commonancestral gene due to the conservation of their structure and catalyticfunction. Almost all kinases contain a similar 250-300 amino acidcatalytic domain. The kinases can be categorized into families by thesubstrates they phosphorylate (e.g., protein-tyrosine,protein-serine/threonine, lipids, etc.). Sequence motifs have beenidentified that generally correspond to each of these families (see,e.g., Hanks & Hunter, (1995), FASEB J. 9:576-596; Knighton et al.,(1991), Science 253:407-414; Hiles et al., (1992), Cell 70:419-429; Kunzet al., (1993), Cell 73:585-596; Garcia-Bustos et al., (1994), EMBO J.13:2352-2361).

JAK kinases (JAnus Kinases) are a family of cytoplasmic protein tyrosinekinases including JAK1, JAK2, JAK3 and TYK2. Each of the JAK kinases isselective for the receptors of certain cytokines, though multiple JAKkinases can be affected by particular cytokine or signaling pathways.Studies suggest that JAK3 associates with the common gamma (γc) chain ofthe various cytokine receptors. JAK3 in particular selectively binds toreceptors and is part of the cytokine signaling pathway for IL-2, IL-4,IL-7, IL-9, IL-15 and IL-21. JAK1 interacts with, among others, thereceptors for cytokines IL-2, IL-4, IL-7, IL-9 and IL-21, while JAK2interacts with, among others, the receptors for IL-9 and TNF-α. Upon thebinding of certain cytokines to their receptors (e.g., IL-2, IL-4, IL-7,IL-9, IL-15 and IL-21), receptor oligomerization occurs, resulting inthe cytoplasmic tails of associated JAK kinases being brought intoproximity and facilitating the trans-phosphorylation of tyrosineresidues on the JAK kinase. This trans-phosphorylation results in theactivation of the JAK kinase.

Phosphorylated JAK kinases bind various STAT (Signal Transducer andActivator of Transcription) proteins. STAT proteins, which are DNAbinding proteins activated by phosphorylation of tyrosine residues,function both as signaling molecules and transcription factors andultimately bind to specific DNA sequences present in the promoters ofcytokine-responsive genes (Leonard et al., (2000), J. Allergy Clin.Immunol. 105:877-888). JAK/STAT signaling has been implicated in themediation of many abnormal immune responses such as allergies, asthma,autoimmune diseases such as transplant (allograft) rejection, rheumatoidarthritis, amyotrophic lateral sclerosis and multiple sclerosis, as wellas in solid and hematologic malignancies such as leukemia and lymphomas.For a review of the pharmaceutical intervention of the JAK/STAT pathwaysee Frank, (1999), Mol. Med. 5:432:456 and Seidel et al., (2000),Oncogene 19:2645-2656.

JAK3 in particular has been implicated in a variety of biologicalprocesses. For example, the proliferation and survival of murine mastcells induced by IL-4 and IL-9 have been shown to be dependent on JAK3-and gamma chain-signaling (Suzuki et al., (2000), Blood 96:2172-2180).JAK3 also plays a crucial role in IgE receptor-mediated mast celldegranulation responses (Malaviya et al., (1999), Biochem. Biophys. Res.Commun. 257:807-813), and inhibition of JAK3 kinase has been shown toprevent type I hypersensitivity reactions, including anaphylaxis(Malaviya et al., (1999), J. Biol. Chem. 274:27028-27038). JAK3inhibition has also been shown to result in immune suppression forallograft rejection (Kirken, (2001), Transpl. Proc. 33:3268-3270). JAK3kinases have also been implicated in the mechanism involved in early andlate stages of rheumatoid arthritis (Muller-Ladner et al., (2000), J.Immunal. 164:3894-3901); familial amyotrophic lateral sclerosis (Trieuet al., (2000), Biochem Biophys. Res. Commun. 267:22-25); leukemia(Sudbeck et al., (1999), Clin. Cancer Res. 5:1569-1582); mycosisfungoides, a form of T-cell lymphoma (Nielsen et al., (1997), Prac.Natl. Acad. Sci. USA 94:6764-6769); and abnormal cell growth (Yu et al.,(1997), J. Immunol. 159:5206-5210; Catlett-Falcone et al., (1999),Immunity 10:105-115).

The JAK kinases, including JAK3, are abundantly expressed in primaryleukemic cells from children with acute lymphoblastic leukemia, the mostcommon form of childhood cancer, and studies have correlated STATactivation in certain cells with signals regulating apoptosis (Demoulinet al., (1996), Mol. Cell. Biol. 16:4710-6; Jurlander et al., (1997),Blood. 89:4146-52; Kaneko et al., (1997), Clin. Exp. Immun. 109:185-193;and Nakamura et al., (1996), J. Biol. Chem. 271:19483-8). They are alsoknown to be important to lymphocyte differentiation, function andsurvival. JAK-3 in particular plays an essential role in the function oflymphocytes, macrophages, and mast cells. Given the importance of thisJAK kinase, compounds which modulate the JAK pathway, including thoseselective for JAK3, can be useful for treating diseases or conditionswhere the function of lymphocytes, macrophages, or mast cells isinvolved (Kudlacz et al., (2004) Am. J. Transplant 4:51-57; Changelian(2003) Science 302:875-878). Conditions in which targeting of the JAKpathway or modulation of the JAK kinases, particularly JAK3, arecontemplated to be therapeutically useful include, leukemia, lymphoma,transplant rejection (e.g., pancreas islet transplant rejection, bonemarrow transplant applications (e.g., graft-versus-host disease),autoimmune diseases (e.g., diabetes), and inflammation (e.g., asthma,allergic reactions). Conditions which can benefit for inhibition of JAK3are discussed in greater detail below.

In view of the numerous conditions that are contemplated to benefit bytreatment involving modulation of the JAK pathway it is immediatelyapparent that new compounds that modulate JAK pathways and methods ofusing these compounds should provide substantial therapeutic benefits toa wide variety of patients. Provided herein are novel2,4-pyrimidinediamine compounds for use in the treatment of conditionsin which targeting of the JAK pathway or inhibition of JAK kinases,particularly JAK3, are therapeutically useful.

Patents and patent applications related to modulation of the JAK pathwayinclude: U.S. Pat. Nos. 5,728,536; 6,080,747; 6,080,748; 6,133,305;6,177,433; 6,210,654; 6,313,130; 6,316,635; 6,433,018; 6,486,185;6,506,763; 6,528,509; 6,593,357; 6,608,048; 6,610,688; 6,635,651;6,677,368; 6,683,082; 6,696,448; 6,699,865; 6,777,417; 6,784,195;6,825,190; 6,506,763; 6,784,195; 6,528,509; 6,608,048; 7,105,529;6,699,865; 6,825,190; 6,815,439; 6,949,580; 7,056,944; 6,998,391;7,074,793; 6,969,760; 7,122,552; U.S. Pat. App. Pub. No. 2001/0007033A1; 2002/0115173 A1; 2002/0137141 A1; 2004/0102455 A1; 2004/0142404 A1;2004/0147507 A1; and 2004/0214817 A1; and International patentapplications WO 95/03701A1; WO 99/15500A1; WO 00/00202A1; WO 00/10981A1;WO 00/47583A1; WO 00/51587A2; WO 00/55159A2; WO 01/42246A2; WO01/45641A2; WO 01/52892A2; WO 01/56993A2; WO 01/57022A2; WO 01/72758A1;WO 02/00661A1; WO 02/43735A1; WO 02/48336A2; WO 02/060492A1; WO02/060927A1; WO 02/096909A1; WO 02/102800A1; WO 03/020698A2; WO03/048162A1; WO 03/101989A1; WO 2004/016597A2; WO 2004/041789A1; WO2004/041810A1; WO 2004/041814A1; WO 2004/046112A2; WO 2004/046120A2; WO2004/047843A1; WO 2004/058749A1; WO 2004/058753A1; WO 2004/085388A2; WO2004/092154A1; WO 2005/009957A1; WO 2005/016344A1; WO 2005/028475A2; andWO 2005/033107A1.

Patents and patent applications describing substituted pyrimidinediaminecompounds include: U.S. Patent Application Publication No.2004/0029902A1, international application Serial No. PCT/US03/03022filed Jan. 31, 2003 (WO 03/063794), U.S. application Ser. No. 10/631,029filed Jul. 29, 2003, international application Serial No. PCT/US03/24087(WO 04/014382), U.S. Patent Application Publication No. 2005/0234049A1,international application Serial No. PCT/US2004/24716 (WO 05/016893),U.S. Patent Application Publication No. 2006/0293311A1, andinternational application Serial No. PCT/US2006/133426 (WO 06/133426)filed Jun. 8, 2006, the disclosures of which are incorporated herein byreference. Substituted pyrimidinediamine compounds are also described ininternational patent application publication numbers: WO 02/059110, WO03/074515, WO 03/106416, WO 03/066601, WO 03/063794, WO 04/046118, WO05/016894, WO 05/122294, WO 05/066156, WO 03/002542, WO 03/030909, WO00/39101, WO 05/037800 and U.S. Pat. Pub. No. 2003/0149064.

All of the above publications are herein incorporated by reference intheir entirety to the same extent as if each individual publication wasspecifically and individually indicated to be incorporated by referencein its entirety.

SUMMARY OF THE INVENTION

This invention is directed to compounds, prodrugs, and methods of usingthese compounds and prodrugs thereof in the treatment of conditions inwhich modulation of the JAK pathway or inhibition of JAK kinases,particularly JAK3, will be therapeutically useful.

In one implementation, the present invention provides a compound offormula I, a solvate, prodrug or pharmaceutically acceptable saltthereof:

wherein:

-   -   ring A is aryl, or heteroaryl;    -   ring B is aryl, heteroaryl, cycloalkyl, or heterocyclic;    -   p is 0, 1, 2 or 3 when ring A is monocyclic or p is 0, 1, 2, 3,        4, or 5 when ring A contains multiple rings;    -   q is 0, 1, 2 or 3 when ring B is monocyclic or q is 0, 1, 2, 3,        4, or 5 when ring B contains multiple rings;    -   X is selected from the group consisting of alkyl, substituted        alkyl, hydroxy, alkoxy, substituted alkoxy, amino, substituted        amino, carboxyl, carboxyl ester, cyano, halo, nitro, alkenyl,        substituted alkenyl, alkynyl, and substituted alkynyl;    -   W is —SO₂N(R⁴)R⁵, -alk-SO₂N(R⁴)R⁵, —N(R⁴)SO₂R⁵, or        -alk-N(R⁴)SO₂R⁵;    -   -alk- is selected from the group consisting of straight or        branched chain C₁₋₆ alkylene group, and straight or branched        chain substituted C₁₋₆ alkylene group;    -   R¹ is hydrogen or C₁₋₃ alkyl;    -   each R² independently is selected from the group consisting of        alkyl, substituted alkyl, alkoxy, substituted alkoxy, alkenyl,        substituted alkenyl, alkynyl, substituted alkynyl, cycloalkenyl,        substituted cycloalkenyl, alkynyloxy, amino, substituted amino,        aryl, substituted aryl, aryloxy, substituted aryloxy, cyano,        cycloalkyl, substituted cycloalkyl, cycloalkoxy, substituted        cycloalkoxy, heteroaryl, substituted heteroaryl, heteroaryloxy,        substituted heteroaryloxy, heterocyclic, substituted        heterocyclic, heterocyclyloxy, substituted heterocyclyloxy,        aminocarbonyl, aminocarbonyloxy, carboxyl, carboxyl ester,        (carboxyl ester)oxy, nitro, halo, and oxo, wherein if R² is oxo,        then the oxo substituent is attached to a nonaromatic portion of        ring A; or        -   R⁴ and one of R² together with the intervening atoms bound            thereto form a heterocyclic or a substituted heterocyclic            fused to ring A; or        -   R⁵ and one of R² together with the intervening atoms bound            thereto form a heterocyclic or a substituted heterocyclic            fused to ring A; or    -   each R³ independently is selected from the group consisting of        alkyl, substituted alkyl, alkoxy, substituted alkoxy, alkenyl,        substituted alkenyl, alkynyl, substituted alkynyl, alkynyloxy,        amino, substituted amino, aryl, substituted aryl, aryloxy,        substituted aryloxy, cyano, cycloalkyl, substituted cycloalkyl,        cycloalkoxy, substituted cycloalkoxy, heteroaryl, substituted        heteroaryl, heteroaryloxy, substituted heteroaryloxy,        heterocyclic, substituted heterocyclic, heterocyclyloxy,        substituted heterocyclyloxy, aminocarbonyl, aminocarbonyloxy,        carboxyl, carboxyl ester, (carboxyl ester)oxy, nitro, and halo;        or    -   R⁴ is selected from the group consisting of hydrogen, alkyl,        substituted alkyl, cycloalkyl, substituted cycloalkyl,        heterocyclic, substituted heterocyclic, aryl, substituted aryl,        heteroaryl, substituted heteroaryl, acyl and M⁺, wherein M⁺ is a        counterion selected from the group consisting of K⁺, Na⁺, Li⁺        and ⁺N(R⁸)₄, wherein R⁸ is hydrogen or alkyl, and the nitrogen        of —SO₂N(R⁴)R⁵ or —N(R⁴)SO₂R⁵ is N⁻;    -   R⁵ is selected from the group consisting of hydrogen, alkyl,        substituted alkyl, amino, alkylamino, dialkylamino,        cycloalkylamino, cycloalkyl, substituted cycloalkyl,        heterocyclic, substituted heterocyclic, aryl, substituted aryl,        heteroaryl, substituted heteroaryl, and acyl; or    -   R⁴ and R⁵ together with the intervening atom or atoms bound        thereto form a heterocyclic or a substituted heterocyclic group.

In a preferred implementation, when W is —SO₂N(R⁴)R⁵, then W is notbound to an atom adjacent to the atom of ring A that is bound to N4 ofthe pyrimidine in formula I. Preferably, when W is —N(R⁴)SO₂R⁵, then Ais not chromanyl. Also preferably, when W is —SO₂N(R⁴)R⁵ and X is haloor alkyl, then R³ is not methoxy. Still preferably, when W is—SO₂N(R⁴)R⁵ and X is bromo, then R³ is not alkoxy, substituted alkoxy orhalo.

In a preferred implementation, when W is —SO₂N(R⁴)R⁵, then W is notbound to an atom adjacent to the atom of ring A that is bound to N4 ofthe pyrimidine in formula I, which is illustrated as follows:

In this implementation, A is phenyl. Therefore, W will not besubstituted on an atom shown by *, ortho to the carbon attached to N4 ofthe pyrimidinediamine core. Similarly, when ring A is an aromatic moietyother than phenyl, W is not substituted on an atom adjacent to the atomof ring A that is attached to N4 on the prymidinediamine core.

In other implementations, R⁴ is selected from a variety of moietiesincluding a counterion, designated as M⁺. Although M⁺ is preferably amonovalent cation, such as, K⁺, Na⁺, or Li⁺, it can however also be adivalent cation with appropriate counterions, for example, two of theparent drug mono anion, one of parent/one of other counter anion, onedivalent parent anion with one divalent cation, etc.

In another implementation, the present invention provides a compound offormula II, a solvate, prodrug, or pharmaceutically acceptable saltthereof:

wherein R¹, R², R³, R⁴, R⁵, X, p and q are as defined above and -alk- isa straight chain C₁₋₆ alkylene group.

In one preferred implementation, the compound is a compound representedby formula IIa, a solvate, prodrug, or pharmaceutically acceptable saltthereof:

wherein R¹, R², R³, R⁴, R⁵, X, p and q are as defined above, wherein—SO₂N(R⁴)R⁵ is attached to the phenyl ring at the 3-, 4-, or 5-position;and provided that

-   -   a) when X is halo or alkyl, then R³ is not methoxy; and    -   b) when X is bromo, then R³ is not alkoxy, substituted alkoxy or        halo.

In another implementation, this invention provides a compoundrepresented by formula III, a solvate, prodrug, or pharmaceuticallyacceptable salt thereof:

wherein R², R³, X, p and q, are as defined above; W is —N(R⁴)SO₂R⁵, or-alk-N(R⁴)SO₂R⁵ wherein R⁴ and R⁵ are as defined above; and -alk- is astraight chain C₁₋₆ alkylene.

In one preferred implementation, the compound is a compound representedby formula IIIa, a solvate, prodrug, or pharmaceutically acceptable saltthereof:

wherein R², R³, R⁴, R⁵, X, p and q, are as defined above, and -alk- is astraight chain C₁₋₆ alkylene.

In yet another implementation, this invention provides a compoundrepresented by formula IV, a solvate, prodrug, or pharmaceuticallyacceptable salt thereof:

wherein Q is carbon or nitrogen, and R³, R⁴, R⁵, X, -alk-, and q are asdefined above.

In another implementation, this invention provides a compoundrepresented by formula V, a solvate, prodrug, or pharmaceuticallyacceptable salt thereof:

wherein Q is carbon, or nitrogen, and R³, R⁴, R⁵, X, -alk-, and q are asdefined above.

In yet another implementation, this invention provides a compound offormula VI, a solvate, prodrug, or pharmaceutically acceptable saltthereof:

wherein X, R³ and R⁵ are as defined above.

In yet another implementation, this invention provides a compound offormula VII, a solvate, prodrug, or pharmaceutically acceptable saltthereof:

wherein X, Z, R³ and R⁵ are as defined above.

In yet another implementation, this invention provides a compound offormula VIII, a solvate, prodrug, or pharmaceutically acceptable saltthereof:

wherein X, Z, and R³ are as defined above.

In another implementation, this invention provides a method ofinhibiting an activity of a JAK kinase, comprising contacting the JAKkinase with an amount of a compound of this invention effective toinhibit an activity of the JAK kinase.

In another implementation, this invention provides a method ofinhibiting an activity of a JAK kinase, comprising contacting the JAKkinase with an amount of any compound of this invention, preferably, acompound of formula I effective to inhibit an activity of the JAKkinase:

a solvate, prodrug or pharmaceutically acceptable salt thereof, whereinring A, ring B, R¹, R², R³, X, W, p and q are as defined above forformula I.

In a preferred implementation, the compound contacted with the JAKkinase is selected from the group consisting of a compound of formulaII, III, IV, and V.

In another implementation, this invention provides a method ofinhibiting an activity of a JAK kinase, comprising contacting in vitro aJAK3 kinase with an amount of a compound of this invention to inhibit anactivity of the JAK kinase.

In another implementation, this invention provides a method ofinhibiting an activity of a JAK kinase, comprising contacting in vitro aJAK3 kinase with an amount of any compound of this invention,preferably, a compound of formula I effective to inhibit an activity ofthe JAK kinase:

a solvate, prodrug or pharmaceutically acceptable salt thereof, whereinring A, ring B, R¹, R², R³, X, W, p and q are as defined above forformula I.

In a preferred implementation, the compound contacted in vitro with theJAK3 kinase is selected from the group consisting of a compound offormula II, III, IV, and V.

In another implementation, this invention provides a method of treatinga T-cell mediated autoimmune disease, comprising administering to apatient suffering from such an autoimmune disease an amount of acompound of this invention effective to treat the autoimmune disease.

In another implementation, this invention provides a method of treatingor preventing allograft transplant rejection in a transplant recipient,comprising administering to the transplant recipient an amount of acompound of this invention effective to treat or prevent the allografttransplant rejection.

In another implementation, this invention provides a method of treatingor preventing a Type IV hypersensitivity reaction, comprisingadministering to a subject an amount of a compound of this inventioneffective to treat or prevent the hypersensitivity reaction.

In another implementation, this invention provides a method ofinhibiting a signal transduction cascade in which JAK3 kinase plays arole, comprising contacting a cell expressing a receptor involved insuch a signaling cascade with a compound of this invention, as describedabove.

In another implementation, this invention provides a method ofinhibiting a signal transduction cascade in which JAK3 kinase plays arole, comprising contacting a cell expressing a receptor involved insuch a signaling cascade with any compound of this invention,preferably, a compound of formula I effective to inhibit a signaltransduction cascade in which JAK3 kinase plays a role:

a solvate, prodrug or pharmaceutically acceptable salt thereof, whereinring A, ring B, R¹, R², R³, X, W, p and q are as defined above forformula I.

In a preferred implementation, the compound contacted with the cell isselected from the group consisting of a compound of formula II, III, IV,and V.

In another implementation, this invention provides a method of treatingor preventing a JAK kinase-mediated disease, comprising administering toa subject an amount of a compound of this invention effective to treator prevent the JAK kinase-mediated disease.

In another implementation, this invention provides a method of treatingor preventing a JAK kinase-mediated disease, comprising administering toa subject an amount of any compound of this invention, preferably, acompound of formula I effective to treat or prevent the JAKkinase-mediated disease:

a solvate, prodrug or pharmaceutically acceptable salt thereof, whereinring A, ring B, R¹, R², R³, X, W, p and q are as defined above forformula I.

In a preferred implementation, the compound administered to the subjectis selected from the group consisting of a compound of formula II, III,IV, and V.

In another implementation, this invention provides a pharmaceuticalformulation comprising a compound selected from the compounds of thisinvention, as described above.

In another implementation, this invention provides a kit comprising acompound selected from the compounds of this invention or a prodrugthereof, packaging, and instructions for use.

It will be appreciated by one of skill in the art that theimplementations summarized above may be used together in any suitablecombination to generate implementations not expressly recited above andthat such implementations are considered to be part of the presentinvention.

DETAILED DESCRIPTION A. Overview

The invention encompasses compounds having formula I and thecompositions and methods using these compounds in the treatment ofconditions in which modulation of the JAK pathway or inhibition of JAKkinases, particularly JAK3, are therapeutically useful.

B. Definitions

As used herein, the following definitions shall apply unless otherwiseindicated.

“Alkyl” refers to monovalent saturated aliphatic hydrocarbyl groupshaving from 1 to 10 carbon atoms and preferably 1 to 6 carbon atoms.This term includes, by way of example, linear and branched hydrocarbylgroups such as methyl (CH₃—), ethyl (CH₃CH₂—), n-propyl (CH₃CH₂CH₂—),isopropyl ((CH₃)₂CH—), n-butyl (CH₃CH₂CH₂CH₂—), isobutyl ((CH₃)₂CHCH₂—),sec-butyl ((CH₃)(CH₃CH₂)CH—), t-butyl ((CH₃)₃C—), n-pentyl(CH₃CH₂CH₂CH₂CH₂—), and neopentyl ((CH₃)₃CCH₂—).

“Substituted alkyl” refers to an alkyl group having from 1 to 5hydrogens replaced with substituents selected from the group consistingof alkoxy, substituted alkoxy, acyl, acylamino, acyloxy, amino,substituted amino, aminocarbonyl, aminothiocarbonyl, aminocarbonylamino,aminothiocarbonylamino, aminocarbonyloxy, amidino, aryl, substitutedaryl, aryloxy, substituted aryloxy, arylthio, substituted arylthio,carboxyl, carboxyl ester, (carboxyl ester)amino, (carboxyl ester)oxy,cyano, cycloalkyl, substituted cycloalkyl, cycloalkyloxy, substitutedcycloalkyloxy, cycloalkylthio, substituted cycloalkylthio, cycloalkenyl,substituted cycloalkenyl, cycloalkenyloxy, substituted cycloalkenyloxy,cycloalkenylthio, substituted cycloalkenylthio, guanidino, substitutedguanidino, halo, hydroxy, heteroaryl, substituted heteroaryl,heteroaryloxy, substituted heteroaryloxy, heteroarylthio, substitutedheteroarylthio, heterocyclic, substituted heterocyclic, heterocyclyloxy,substituted heterocyclyloxy, heterocyclylthio, substitutedheterocyclylthio, nitro, SO₃H, sulfonyl, sulfonyloxy, thioacyl, thiol,alkylthio, and substituted alkylthio, wherein said substituents aredefined herein. In some implementations, the alkyl has 1 to 3 of theaforementioned groups. In other implementations, the alkyl has 1 to 2 ofthe aforementioned groups.

“Alkylene” refers to divalent saturated aliphatic hydrocarbyl groupspreferably having from 1 to 6 and more preferably 1 to 3 carbon atomsthat are either straight-chained or branched. This term is exemplifiedby groups such as methylene (—CH₂—), ethylene (—CH₂CH₂—), n-propylene(—CH₂CH₂CH₂—), iso-propylene (—CH₂CH(CH₃)—) or (—CH(CH₃)CH₂—), and thelike.

“Substituted alkylene” refers to an alkylene group having from 1 to 3hydrogens replaced with substituents selected from the group consistingof alkyl, substituted alkyl, alkoxy, substituted alkoxy, acyl,acylamino, acyloxy, amino, substituted amino, aminocarbonyl, aryl,substituted aryl, aryloxy, substituted aryloxy, cyano, halogen,hydroxyl, nitro, carboxyl, carboxyl ester, cycloalkyl, substitutedcycloalkyl, heteroaryl, substituted heteroaryl, heterocyclic,substituted heterocyclic, and oxo wherein said substituents are definedherein. In some implementations, the alkylene has 1 to 2 of theaforementioned groups. It is to be noted that when the alkylene issubstituted by an oxo group, 2 hydrogens attached to the same carbon ofthe alkylene group are replaced by “═O”.

“Alkoxy” refers to the group —O-alkyl, wherein alkyl is as definedherein. Alkoxy includes methoxy, ethoxy, n-propoxy, isopropoxy,n-butoxy, t-butoxy, sec-butoxy, n-pentoxy, and the like.

“Substituted alkoxy” refers to the group —O-(substituted alkyl), whereinsubstituted alkyl is as defined herein.

“Acyl” refers to the groups H—C(O)—, alkyl-C(O)—, substitutedalkyl-C(O)—, alkenyl-C(O)—, substituted alkenyl-C(O)—, alkynyl-C(O)—,substituted alkynyl-C(O)—, cycloalkyl-C(O)—, substitutedcycloalkyl-C(O)—, cycloalkenyl-C(O)—, substituted cycloalkenyl-C(O)—,aryl-C(O)—, substituted aryl-C(O)—, heteroaryl-C(O)—, substitutedheteroaryl-C(O)—, heterocyclic-C(O)—, and substitutedheterocyclic-C(O)—, wherein alkyl, substituted alkyl, alkenyl,substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl,substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl,substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, andsubstituted heterocyclic are as defined herein. Acyl includes the“acetyl” group CH₃C(O)—.

“Acylamino” refers to the groups —NR²⁰C(O)alkyl, —NR²⁰C(O)substitutedalkyl, —NR²⁰C(O)cycloalkyl, —NR²⁰C(O)substituted cycloalkyl,—NR²⁰C(O)cycloalkenyl, —NR²⁰C(O)substituted cycloalkenyl,—NR²⁰C(O)alkenyl, —NR²⁰C(O)substituted alkenyl, —NR²⁰C(O)alkynyl,—NR²⁰C(O)substituted alkynyl, —NR²⁰C(O)aryl, —NR²⁰C(O)substituted aryl,—NR²⁰C(O)heteroaryl, —NR²⁰C(O)substituted heteroaryl,—NR²⁰C(O)heterocyclic, and —NR²⁰C(O)substituted heterocyclic, whereinR²⁰ is hydrogen or alkyl and wherein alkyl, substituted alkyl, alkenyl,substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl,substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl,substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, andsubstituted heterocyclic are as defined herein.

“Acyloxy” refers to the groups alkyl-C(O)O—, substituted alkyl-C(O)O—,alkenyl-C(O)O—, substituted alkenyl-C(O)O—, alkynyl-C(O)O—, substitutedalkynyl-C(O)O—, aryl-C(O)O—, substituted aryl-C(O)O—, cycloalkyl-C(O)O—,substituted cycloalkyl-C(O)O—, cycloalkenyl-C(O)O—, substitutedcycloalkenyl-C(O)O—, heteroaryl-C(O)O—, substituted heteroaryl-C(O)O—,heterocyclic-C(O)O—, and substituted heterocyclic-C(O)O—, wherein alkyl,substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substitutedalkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substitutedcycloalkenyl, aryl, substituted aryl, heteroaryl, substitutedheteroaryl, heterocyclic, and substituted heterocyclic are as definedherein.

“Amino” refers to the group —NH₂.

“Substituted amino” refers to the group —NR²¹R²², wherein R²¹ and R²²independently are selected from the group consisting of hydrogen, alkyl,substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substitutedalkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl,cycloalkenyl, substituted cycloalkenyl, heteroaryl, substitutedheteroaryl, heterocyclic, and substituted heterocyclic, or R²¹ and R²²are joined together with the nitrogen bound thereto to form aheterocyclic or substituted heterocyclic group, and wherein alkyl,substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substitutedalkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substitutedcycloalkenyl, aryl, substituted aryl, heteroaryl, sulfonyl, substitutedheteroaryl, heterocyclic, and substituted heterocyclic are as definedherein. R²¹ and R²² are not both hydrogen. When R²¹ is hydrogen and R²²is alkyl, the substituted amino group is sometimes referred to herein as“alkylamino.” When R²¹ and R²² are alkyl, the substituted amino group issometimes referred to herein as “dialkylamino.” When referring to amonosubstituted amino, it is meant that either R²¹ or R²² is hydrogen,but not both. When referring to a disubstituted amino, it is meant thatneither R²¹ nor R²² is hydrogen.

“Aminocarbonyl” refers to the group —C(O)NR²¹R²², wherein R²¹ and R²²independently are selected from the group consisting of hydrogen, alkyl,substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substitutedalkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl,cycloalkenyl, substituted cycloalkenyl, heteroaryl, substitutedheteroaryl, heterocyclic, and substituted heterocyclic, or R²¹ and R²²are joined together with the nitrogen bound thereto to form aheterocyclic or substituted heterocyclic group, and wherein alkyl,substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substitutedalkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substitutedcycloalkenyl, aryl, substituted aryl, heteroaryl, substitutedheteroaryl, heterocyclic, and substituted heterocyclic are as definedherein.

“Aminothiocarbonyl” refers to the group —C(S)NR²¹R²², wherein R²¹ andR²² independently are selected from the group consisting of hydrogen,alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl,substituted alkynyl, aryl, substituted aryl, cycloalkyl, substitutedcycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl,substituted heteroaryl, heterocyclic, and substituted heterocyclic, orR²¹ and R²² are joined together with the nitrogen bound thereto to forma heterocyclic or substituted heterocyclic group, and wherein alkyl,substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substitutedalkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substitutedcycloalkenyl, aryl, substituted aryl, heteroaryl, substitutedheteroaryl, heterocyclic, and substituted heterocyclic are as definedherein.

“Aminocarbonylamino” refers to the group —NR²⁰C(O)NR²¹R²², wherein R²⁰is hydrogen or alkyl and R²¹ and R²² independently are selected from thegroup consisting of hydrogen, alkyl, substituted alkyl, alkenyl,substituted alkenyl, alkynyl, substituted alkynyl, aryl, substitutedaryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substitutedcycloalkenyl, heteroaryl, substituted heteroaryl, heterocyclic, andsubstituted heterocyclic, or R²¹ and R²² are joined together with thenitrogen bound thereto to form a heterocyclic or substitutedheterocyclic group, and wherein alkyl, substituted alkyl, alkenyl,substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl,substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl,substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic andsubstituted heterocyclic are as defined herein.

“Aminothiocarbonylamino” refers to the group —NR²⁰C(S)NR²¹R²², whereinR²⁰ is hydrogen or alkyl and R²¹ and R²² independently are selected fromthe group consisting of hydrogen, alkyl, substituted alkyl, alkenyl,substituted alkenyl, alkynyl, substituted alkynyl, aryl, substitutedaryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substitutedcycloalkenyl, heteroaryl, substituted heteroaryl, heterocyclic, andsubstituted heterocyclic, or R²¹ and R²² are joined together with thenitrogen bound thereto to form a heterocyclic or substitutedheterocyclic group, and wherein alkyl, substituted alkyl, alkenyl,substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl,substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl,substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic andsubstituted heterocyclic are as defined herein.

“Aminocarbonyloxy” refers to the group —O—C(O)NR²¹R²², wherein R²¹ andR²² independently are selected from the group consisting of hydrogen,alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl,substituted alkynyl, aryl, substituted aryl, cycloalkyl, substitutedcycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl,substituted heteroaryl, heterocyclic, and substituted heterocyclic, orR²¹ and R²² are joined together with the nitrogen bound thereto to forma heterocyclic or substituted heterocyclic group, and wherein alkyl,substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substitutedalkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substitutedcycloalkenyl, aryl, substituted aryl, heteroaryl, substitutedheteroaryl, heterocyclic and substituted heterocyclic are as definedherein.

“Aminosulfonyl” refers to the group —SO₂NR²¹R²², wherein R²¹ and R²²independently are selected from the group consisting of hydrogen, alkyl,substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substitutedalkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl,cycloalkenyl, substituted cycloalkenyl, heteroaryl, substitutedheteroaryl, heterocyclic, substituted heterocyclic and where R²¹ and R²²are optionally joined together with the nitrogen bound thereto to form aheterocyclic or substituted heterocyclic group and alkyl, substitutedalkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl,cycloalkyl, substituted cycloalkyl, cycloalkenyl, substitutedcycloalkenyl, aryl, substituted aryl, heteroaryl, substitutedheteroaryl, heterocyclic and substituted heterocyclic are as definedherein.

“Aminosulfonyloxy” refers to the group —O—SO₂NR²¹R²², wherein R²¹ andR²² independently are selected from the group consisting of hydrogen,alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl,substituted alkynyl, aryl, substituted aryl, cycloalkyl, substitutedcycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl,substituted heteroaryl, heterocyclic, and substituted heterocyclic; R²¹and R²² are optionally joined together with the nitrogen bound theretoto form a heterocyclic or substituted heterocyclic group; and alkyl,substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substitutedalkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substitutedcycloalkenyl, aryl, substituted aryl, heteroaryl, substitutedheteroaryl, heterocyclic, and substituted heterocyclic are as definedherein.

“Aminosulfonylamino” refers to the group —NR²⁰—SO₂NR²¹R²², wherein R²⁰is hydrogen or alkyl and R²¹ and R²² independently are selected from thegroup consisting of hydrogen, alkyl, substituted alkyl, alkenyl,substituted alkenyl, alkynyl, substituted alkynyl, aryl, substitutedaryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substitutedcycloalkenyl, heteroaryl, substituted heteroaryl, heterocyclic, andsubstituted heterocyclic and where R²¹ and R²² are optionally joinedtogether with the nitrogen bound thereto to form a heterocyclic orsubstituted heterocyclic group, and wherein alkyl, substituted alkyl,alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl,substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl,substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic andsubstituted heterocyclic are as defined herein.

“Sulfonylamino” refers to the group —NR²¹SO₂R²², wherein R²¹ and R²²independently are selected from the group consisting of hydrogen, alkyl,substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substitutedalkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl,cycloalkenyl, substituted cycloalkenyl, heteroaryl, substitutedheteroaryl, heterocyclic, and substituted heterocyclic and where R²¹ andR²² are optionally joined together with the atoms bound thereto to forma heterocyclic or substituted heterocyclic group, and wherein alkyl,substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substitutedalkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substitutedcycloalkenyl, aryl, substituted aryl, heteroaryl, substitutedheteroaryl, heterocyclic, and substituted heterocyclic are as definedherein.

“Amidino” refers to the group —C(═NR³⁰)NR³¹R³², wherein R³¹ and R³²independently are selected from the group consisting of hydrogen, alkyl,substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substitutedalkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl,cycloalkenyl, substituted cycloalkenyl, heteroaryl, substitutedheteroaryl, heterocyclic, and substituted heterocyclic, or R³¹ and R³²are joined together with the nitrogen bound thereto to form aheterocyclic or substituted heterocyclic group. R³⁰ is selected from thegroup consisting of hydrogen, alkyl, substituted alkyl, alkenyl,substituted alkenyl, alkynyl, substituted alkynyl, cycloalkynyl,substituted cycloalkynyl, aryl, substituted aryl, cycloalkyl,substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl,heteroaryl, substituted heteroaryl, heterocyclic, substitutedheterocyclic, nitro, nitroso, hydroxy, alkoxy, cyano, acyl, —SO₂-alkyland —SO₂-substituted alkyl, wherein alkyl, substituted alkyl, alkenyl,substituted alkenyl, alkynyl, substituted alkynyl, cycloalkynyl,substituted cycloalkynyl, cycloalkyl, substituted cycloalkyl,cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl,heteroaryl, substituted heteroaryl, heterocyclic, substitutedheterocyclic, nitro, nitroso, hydroxy, alkoxy, and cyano are as definedherein.

“Aryl” refers to a monovalent aromatic carbocyclic group of from 6 to 14carbon atoms having a single ring (e.g., phenyl) or multiple condensedrings (e.g., naphthyl or anthryl) which condensed rings may or may notbe aromatic provided that the point of attachment is through an atom ofthe aromatic aryl group. For example, 1,2,3,4-tetrahydronaphthalen-5-yl,9H-fluoren-2-yl, and the like. Preferred aryl groups include phenyl andnaphthyl.

“Substituted aryl” refers to aryl groups having 1 to 5 hydrogensreplaced with substituents independently selected from the groupconsisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl,alkynyl, substituted alkynyl, alkoxy, substituted alkoxy, acyl,acylamino, acyloxy, amino, substituted amino, aminocarbonyl,aminothiocarbonyl, aminocarbonylamino, aminothiocarbonylamino,aminocarbonyloxy, amidino, aryl, substituted aryl, aryloxy, substitutedaryloxy, arylthio, substituted arylthio, carboxyl, carboxyl ester,(carboxyl ester)amino, (carboxyl ester)oxy, cyano, cycloalkyl,substituted cycloalkyl, cycloalkyloxy, substituted cycloalkyloxy,cycloalkylthio, substituted cycloalkylthio, cycloalkenyl, substitutedcycloalkenyl, cycloalkenyloxy, substituted cycloalkenyloxy,cycloalkenylthio, substituted cycloalkenylthio, guanidino, substitutedguanidino, halo, hydroxy, heteroaryl, substituted heteroaryl,heteroaryloxy, substituted heteroaryloxy, heteroarylthio, substitutedheteroarylthio, heterocyclic, substituted heterocyclic, heterocyclyloxy,substituted heterocyclyloxy, heterocyclylthio, substitutedheterocyclylthio, nitro, —SO₃H, sulfonyl, sulfonyloxy, thioacyl, thiol,alkylthio, and substituted alkylthio, wherein said substituents are asdefined herein. In some implementations, the aryl has 1 to 3 of theaforementioned groups. In other implementations, the aryl has 1 to 2 ofthe aforementioned groups. In some implementations, substituted arylincludes compounds containing oxo substituent in the non-aromatic ringfused to the aryl group. For example, 1-oxo-indan-4-yl, wherein thepoint of attachment is through the phenyl ring.

“Aryloxy” refers to the group —O-aryl, wherein aryl is as definedherein, including, by way of example, phenoxy, naphthoxy, and the like.

“Substituted aryloxy” refers to the group —O-(substituted aryl), whereinsubstituted aryl is as defined herein.

“Arylthio” refers to the group —S-aryl, wherein aryl is as definedherein. In other implementations, sulfur may be oxidized to —S(O)— or—SO₂— moieties. Sulfoxides may exist as one or more stereoisomers, e.g.methylsulfinylethane is a chiral molecule having two enantiomeric forms,R and S.

“Substituted arylthio” refers to the group —S-(substituted aryl),wherein substituted aryl is as defined herein. In other implementations,sulfur may be oxidized to —S(O)— or —SO₂— moieties. The sulfoxide mayexist as one or more stereoisomers.

“Alkenyl” refers to straight chain or branched hydrocarbyl groups havingfrom 2 to 6 carbon atoms and preferably 2 to 4 carbon atoms and havingat least 1 and preferably from 1 to 2 sites of vinyl (>C═C<)unsaturation. Such groups are exemplified by vinyl, allyl, andbut-3-en-1-yl. Included within this term are the cis and trans isomersor mixtures of these isomers.

“Substituted alkenyl” refers to alkenyl groups having from 1 to 3substituents selected from the group consisting of alkoxy, substitutedalkoxy, acyl, acylamino, acyloxy, amino, substituted amino,aminocarbonyl, aminothiocarbonyl, aminocarbonylamino,aminothiocarbonylamino, aminocarbonyloxy, aminosulfonyl,aminosulfonyloxy, aminosulfonylamino, amidino, aryl, substituted aryl,aryloxy, substituted aryloxy, arylthio, substituted arylthio, carboxyl,carboxyl ester, (carboxyl ester)amino, (carboxyl ester)oxy, cyano,cycloalkyl, substituted cycloalkyl, cycloalkyloxy, substitutedcycloalkyloxy, cycloalkylthio, substituted cycloalkylthio, cycloalkenyl,substituted cycloalkenyl, cycloalkenyloxy, substituted cycloalkenyloxy,cycloalkenylthio, substituted cycloalkenylthio, guanidino, substitutedguanidino, halo, hydroxy, heteroaryl, substituted heteroaryl,heteroaryloxy, substituted heteroaryloxy, heteroarylthio, substitutedheteroarylthio, heterocyclic, substituted heterocyclic, heterocyclyloxy,substituted heterocyclyloxy, heterocyclylthio, substitutedheterocyclylthio, nitro, SO₃H, sulfonyl, sulfonyloxy, thioacyl, thiol,alkylthio, and substituted alkylthio, wherein said substituents are asdefined herein and with the proviso that any hydroxy substitution is notattached to a vinyl (unsaturated) carbon atom. In some implementations,the alkenyl has 1 to 2 of the aforementioned groups.

“Alkynyl” refers to straight or branched monovalent hydrocarbyl groupshaving from 2 to 6 carbon atoms and preferably 2 to 3 carbon atoms andhaving at least 1 and preferably from 1 to 2 sites of acetylenic —C≡C—unsaturation. Examples of such alkynyl groups include acetylenyl(—C≡CH), and propargyl (—CH₂C≡CH).

“Substituted alkynyl” refers to alkynyl groups having from 1 to 3substituents selected from the group consisting of alkoxy, substitutedalkoxy, acyl, acylamino, acyloxy, amino, substituted amino,aminocarbonyl, aminothiocarbonyl, aminocarbonylamino,aminothiocarbonylamino, aminocarbonyloxy, aminosulfonyl,aminosulfonyloxy, aminosulfonylamino, amidino, aryl, substituted aryl,aryloxy, substituted aryloxy, arylthio, substituted arylthio, carboxyl,carboxyl ester, (carboxyl ester)amino, (carboxyl ester)oxy, cyano,cycloalkyl, substituted cycloalkyl, cycloalkyloxy, substitutedcycloalkyloxy, cycloalkylthio, substituted cycloalkylthio, cycloalkenyl,substituted cycloalkenyl, cycloalkenyloxy, substituted cycloalkenyloxy,cycloalkenylthio, substituted cycloalkenylthio, guanidino, substitutedguanidino, halo, hydroxy, heteroaryl, substituted heteroaryl,heteroaryloxy, substituted heteroaryloxy, heteroarylthio, substitutedheteroarylthio, heterocyclic, substituted heterocyclic, heterocyclyloxy,substituted heterocyclyloxy, heterocyclylthio, substitutedheterocyclylthio, nitro, SO₃H, sulfonyl, sulfonyloxy, thioacyl, thiol,alkylthio, and substituted alkylthio, wherein said substituents are asdefined herein and with the proviso that any hydroxy or thiolsubstitution is not attached to an acetylenic carbon atom. In someimplementations, the alkynyl has 1 to 2 of the aforementioned groups.

“Alkynyloxy” refers to the group —O-alkynyl, wherein alkynyl is asdefined herein. Alkynyloxy includes, by way of example, ethynyloxy,propynyloxy, and the like.

“Carboxyl” or “carboxy” refers to —COOH or salts thereof.

“Carboxyl ester” or “carboxy ester” refers to the groups —C(O)O-alkyl,—C(O)O-substituted alkyl, —C(O)O-alkenyl, —C(O)O-substituted alkenyl,—C(O)O-alkynyl, —C(O)O-substituted alkynyl, —C(O)O-aryl,—C(O)O-substituted aryl, —C(O)O-cycloalkyl, —C(O)O-substitutedcycloalkyl, —C(O)O-cycloalkenyl, —C(O)O-substituted cycloalkenyl,—C(O)O-heteroaryl, —C(O)O-substituted heteroaryl, —C(O)O-heterocyclic,and —C(O)O-substituted heterocyclic, wherein alkyl, substituted alkyl,alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl,substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl,substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, andsubstituted heterocyclic are as defined herein.

“(Carboxyl ester)amino” refers to the groups —NR—C(O)O-alkyl,—NR—C(O)O-substituted alkyl, —NR—C(O)O-alkenyl, —NR—C(O)O-substitutedalkenyl, —NR—C(O)O-alkynyl, —NR—C(O)O-substituted alkynyl,—NR—C(O)O-aryl, —NR—C(O)O-substituted aryl, —NR—C(O)O-cycloalkyl,—NR—C(O)O-substituted cycloalkyl, —NR—C(O)O-cycloalkenyl,—NR—C(O)O-substituted cycloalkenyl, —NR—C(O)O-heteroaryl,—NR—C(O)O-substituted heteroaryl, —NR—C(O)O-heterocyclic, and—NR—C(O)O-substituted heterocyclic, wherein R is alkyl or hydrogen andalkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl,substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl,substituted cycloalkenyl, aryl, substituted aryl, heteroaryl,substituted heteroaryl, heterocyclic, and substituted heterocyclic areas defined herein.

“(Carboxyl ester)oxy” refers to the groups —O—C(O)O-alkyl,—O—C(O)O-substituted alkyl, —O—C(O)O-alkenyl, —O—C(O)O-substitutedalkenyl, —O—C(O)O-alkynyl, —O—C(O)O-substituted alkynyl, —O—C(O)O-aryl,—O—C(O)O-substituted aryl, —O—C(O)O-cycloalkyl, —O—C(O)O-substitutedcycloalkyl, —O—C(O)O-cycloalkenyl, —O—C(O)O-substituted cycloalkenyl,—O—C(O)O-heteroaryl, —O—C(O)O-substituted heteroaryl,—O—C(O)O-heterocyclic, and —O—C(O)O-substituted heterocyclic, whereinalkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl,substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl,substituted cycloalkenyl, aryl, substituted aryl, heteroaryl,substituted heteroaryl, heterocyclic, and substituted heterocyclic areas defined herein.

“Cyano” or “nitrile” refers to the group —CN.

“cycloalkyl” refers to cyclic alkyl groups of from 3 to 13 carbon atomshaving single or multiple cyclic rings including fused, bridged, andspiro ring systems. Examples of cycloalkyl groups include adamantyl,cyclopropyl, cyclobutyl, cyclopentyl, cyclooctyl, and the like. One ormore rings fused to the cycloalkyl group can be aromatic, provided thatthe point of attachment is through the non-aromatic ring, e.g.9H-fluoren-9-yl, 1, 2,3,4-tetrahydronaphthalen-2-yl, and the like.

“Cycloalkenyl” refers to non-aromatic cyclic alkyl groups of from 3 to10 carbon atoms having single or multiple rings and having at least onedouble bond and preferably from 1 to 2 double bonds.

“Cycloalkynyl” refers to non-aromatic cycloalkyl groups of from 7 to 12carbon atoms having single or multiple rings and having at least onetriple bond.

“Cycloalkylene” refers to divalent cycloalkyl groups, wherein cycloalkylis as defined herein.

“Substituted cycloalkylene” refers to cycloalkylene group having from 1to 3 hydrogens replaced with substituents selected from the groupconsisting of alkyl, substituted alkyl, alkoxy, substituted alkoxy,acyl, acylamino, acyloxy, amino, substituted amino, aminocarbonyl, aryl,substituted aryl, aryloxy, substituted aryloxy, cyano, halogen,hydroxyl, nitro, carboxyl, carboxyl ester, cycloalkyl, substitutedcycloalkyl, heteroaryl, substituted heteroaryl, heterocyclic,substituted heterocyclic, and oxo wherein said substituents are asdefined herein. In some implementations, the alkylene has 1 to 2 of theaforementioned groups. It is to be noted that when the cycloalkylene issubstituted by an oxo group, 2 hydrogens attached to the same carbon ofthe cycloalkylene group are replaced by “═O”.

“Substituted cycloalkyl,” “substituted cycloalkenyl,” and “substitutedcycloalkynyl” refer to a cycloalkyl, cycloalkenyl, or cycloalkynyl grouphaving from 1 to 5 substituents selected from the group consisting ofoxo, thioxo, alkyl, substituted alkyl, alkenyl, substituted alkenyl,alkynyl, substituted alkynyl, alkoxy, substituted alkoxy, acyl,acylamino, acyloxy, amino, substituted amino, aminocarbonyl,aminothiocarbonyl, aminocarbonylamino, aminothiocarbonylamino,aminocarbonyloxy, aminosulfonyl, aminosulfonyloxy, aminosulfonylamino,amidino, aryl, substituted aryl, aryloxy, substituted aryloxy, arylthio,substituted arylthio, carboxyl, carboxyl ester, (carboxyl ester)amino,(carboxyl ester)oxy, cyano, cycloalkyl, substituted cycloalkyl,cycloalkyloxy, substituted cycloalkyloxy, cycloalkylthio, substitutedcycloalkylthio, cycloalkenyl, substituted cycloalkenyl, cycloalkenyloxy,substituted cycloalkenyloxy, cycloalkenylthio, substitutedcycloalkenylthio, guanidino, substituted guanidino, halo, hydroxy,heteroaryl, substituted heteroaryl, heteroaryloxy, substitutedheteroaryloxy, heteroarylthio, substituted heteroarylthio, heterocyclic,substituted heterocyclic, heterocyclyloxy, substituted heterocyclyloxy,heterocyclylthio, substituted heterocyclylthio, nitro, —SO₃H, sulfonyl,sulfonyloxy, thioacyl, thiol, alkylthio, and substituted alkylthio,wherein said substituents are as defined herein, provides that anyhydroxy or thiol substitution is not attached to an unsaturated carbonatom. In some implementations, the cycloalkyl or cycloalkenyl has 1 to 3of the aforementioned groups.

“Cycloalkoxy” refers to —O-cycloalkyl.

“Substituted cycloalkoxy” refers to —O-(substituted cycloalkyl).

“Cycloalkylthio” refers to —S-cycloalkyl. In other implementations,sulfur may be oxidized to —S(O)— or —SO₂— moieties. The sulfoxide mayexist as one or more stereoisomers.

“Substituted cycloalkylthio” refers to —S-(substituted cycloalkyl). Inother implementations, sulfur may be oxidized to —S(O)—, or —SO₂—moieties. The sulfoxide may exist as one or more stereoisomers.

“Cycloalkenyloxy” refers to —O-cycloalkenyl.

“Substituted cycloalkenyloxy” refers to —O-(substituted cycloalkenyl).

“Cycloalkenylthio” refers to —S-cycloalkenyl. In other implementations,sulfur may be oxidized to sulfinyl or sulfonyl moieties. The sulfoxidemay exist as one or more stereoisomers.

“Substituted cycloalkenylthio” refers to —S-(substituted cycloalkenyl).In other implementations, sulfur may be oxidized to —S(O)— or —SO₂—moieties. The sulfoxide may exist as one or more stereoisomers.

“Guanidino” refers to the group —NHC(═NH)NH₂.

“Substituted guanidino” refers to the group —NR³³C(═NR³³)N(R³³)₂,wherein each R³³ independently is selected from the group consisting ofhydrogen, alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl,substituted heteroaryl, heterocyclic, and substituted heterocyclic; twoR groups attached to a common guanidino nitrogen atom are optionallyjoined together with the nitrogen bound thereto to form a heterocyclicor substituted heterocyclic group, provided that at least one R is nothydrogen; and said substituents are as defined herein.

“Halo” or “halogen” refers to fluoro, chloro, bromo, and iodo and ispreferably fluoro or chloro.

“Hydroxy” or “hydroxyl” refers to the group —OH.

“Heteroaryl” refers to an aromatic group of from 1 to 10 carbon atomsand 1 to 4 heteroatoms selected from the group consisting of oxygen,nitrogen, and sulfur within the ring. Such heteroaryl groups can have asingle ring (e.g., pyridinyl or furyl) or multiple condensed rings(e.g., indolizinyl or benzothienyl), wherein the condensed rings may ormay not be aromatic and/or contain a heteroatom, provided that the pointof attachment is through an atom of the aromatic group containing theheteroatom. In one implementation, the nitrogen and/or sulfur ringatom(s) of the heteroaryl group are optionally oxidized to provide forthe N-oxide (N→O), sulfinyl, or sulfonyl moieties. Preferred heteroarylsinclude pyridinyl, pyrrolyl, indolyl, thiophenyl, and furanyl.

“Substituted heteroaryl” refers to heteroaryl groups that aresubstituted with from 1 to 5 substituents selected from the groupconsisting of the same group of substituents defined for substitutedaryl. In some implementations, the heteroaryl has 1 to 3 of theaforementioned groups. In other implementations, the heteroaryl has 1 to2 of the aforementioned groups.

“Heteroaryloxy” refers to —O-heteroaryl.

“Substituted heteroaryloxy” refers to the group —O-(substitutedheteroaryl).

“Heteroarylthio” refers to the group —S-heteroaryl. In otherimplementations, sulfur may be oxidized to —S(O)— or —SO₂— moieties. Thesulfoxide may exist as one or more stereoisomers.

“Substituted heteroarylthio” refers to the group —S-(substitutedheteroaryl). In other implementations, sulfur may be oxidized to —S(O)—or —SO₂— moieties. The sulfoxide may exist as one or more stereoisomers.

“Heterocycle,” “heterocyclic,” “heterocycloalkyl,” and “heterocyclyl”refer to a saturated or unsaturated group having a single ring ormultiple condensed rings, including fused bridged and spiro ringsystems, and having from 3 to 15 ring atoms, including 1 to 4 heteroatoms. These ring atoms are selected from the group consisting ofnitrogen, sulfur, or oxygen, wherein, in fused ring systems, one or moreof the rings can be cycloalkyl, aryl, or heteroaryl, provided that thepoint of attachment is through the non-aromatic ring. In oneimplementation, the nitrogen and/or sulfur atom(s) of the heterocyclicgroup are optionally oxidized to provide for the N-oxide, —S(O)—, or—SO₂-moieties.

“Substituted heterocyclic,” “substituted heterocycloalkyl,”and“substituted heterocyclyl” refer to heterocyclyl groups that aresubstituted with from 1 to 5 of the same substituents as defined forsubstituted cycloalkyl. In some implementations, the heterocyclyl has 1to 3 of the aforementioned groups.

“Heterocyclyloxy” refers to the group —O-heterocycyl.

“Substituted heterocyclyloxy” refers to the group —O-(substitutedheterocycyl).

“Heterocyclylthio” refers to the group —S-heterocycyl. In otherimplementations, sulfur may be oxidized to —S(O)— or —SO₂— moieties. Thesulfoxide may exist as one or more stereoisomers.

“Substituted heterocyclylthio” refers to the group —S-(substitutedheterocycyl). In other implementations, sulfur may be oxidized to —S(O)—or —SO₂— moieties. The sulfoxide may exist as one or more stereoisomers.

Examples of heterocycle and heteroaryls include, but are not limited to,azetidine, pyrrole, imidazole, pyrazole, pyridine, pyrazine, pyrimidine,pyridazine, indolizine, isoindole, indole, dihydroindole, indazole,purine, quinolizine, isoquinoline, quinoline, phthalazine,naphthylpyridine, quinoxaline, quinazoline, cinnoline, pteridine,carbazole, carboline, phenanthridine, acridine, phenanthroline,isothiazole, phenazine, isoxazole, phenoxazine, phenothiazine,imidazolidine, imidazoline, piperidine, piperazine, indoline,phthalimide, 1,2,3,4-tetrahydroisoquinoline,4,5,6,7-tetrahydrobenzo[b]thiophene, thiazole, thiazolidine, thiophene,benzo[b]thiophene, morpholinyl, thiomorpholinyl (also referred to asthiamorpholinyl), 1,1-dioxothiomorpholinyl, piperidinyl, pyrrolidine,tetrahydrofuranyl, and the like.

“Nitro” refers to the group —NO₂.

“Nitroso” refers to the group —NO.

“Oxo” refers to the atom (═O).

“Sulfonyl” refers to the group —SO₂-alkyl, —SO₂-substituted alkyl,—SO₂-alkenyl, —SO₂-substituted alkenyl, —SO₂-cycloalkyl,—SO₂-substituted cylcoalkyl, —SO₂-cycloalkenyl, —SO₂-substitutedcycloalkenyl, —SO₂-aryl, —SO₂-substituted aryl, —SO₂-heteroaryl,—SO₂-substituted heteroaryl, —SO₂-heterocyclic, and —SO₂-substitutedheterocyclic, wherein alkyl, substituted alkyl, alkenyl, substitutedalkenyl, alkynyl, substituted alkynyl, cycloalkyl, substitutedcycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substitutedaryl, heteroaryl, substituted heteroaryl, heterocyclic, and substitutedheterocyclic are as defined herein. Sulfonyl includes groups such asmethyl-SO₂—, phenyl-SO₂—, and 4-methylphenyl-SO₂—.

“Sulfonyloxy” refers to the group —OSO₂-alkyl, —OSO₂-substituted alkyl,—OSO₂-alkenyl, —OSO₂-substituted alkenyl, —OSO₂-cycloalkyl,—OSO₂-substituted cylcoalkyl, —OSO₂-cycloalkenyl, —OSO₂-substitutedcycloalkenyl, —OSO₂-aryl, —OSO₂-substituted aryl, —OSO₂-heteroaryl,—OSO₂-substituted heteroaryl, —OSO₂-heterocyclic, and —OSO₂-substitutedheterocyclic, wherein alkyl, substituted alkyl, alkenyl, substitutedalkenyl, alkynyl, substituted alkynyl, cycloalkyl, substitutedcycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substitutedaryl, heteroaryl, substituted heteroaryl, heterocyclic, and substitutedheterocyclic are as defined herein.

“Thioacyl” refers to the groups H—C(S)—, alkyl-C(S)—, substitutedalkyl-C(S)—, alkenyl-C(S)—, substituted alkenyl-C(S)—, alkynyl-C(S)—,substituted alkynyl-C(S)—, cycloalkyl-C(S)—, substitutedcycloalkyl-C(S)—, cycloalkenyl-C(S)—, substituted cycloalkenyl-C(S)—,aryl-C(S)—, substituted aryl-C(S)—, heteroaryl-C(S)—, substitutedheteroaryl-C(S)—, heterocyclic-C(S)—, and substitutedheterocyclic-C(S)—, wherein alkyl, substituted alkyl, alkenyl,substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl,substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl,substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, andsubstituted heterocyclic are as defined herein.

“Thiol” refers to the group —SH.

“Thioxo” refers to the atom (═S).

“Alkylthio” refers to the group —S-alkyl, wherein alkyl is as definedherein. In other implementations, sulfur may be oxidized to —S(O)—. Thesulfoxide may exist as one or more stereoisomers.

“Substituted alkylthio” refers to the group —S-(substituted alkyl),wherein substituted alkyl is as defined herein. In otherimplementations, sulfur may be oxidized to —S(O)—. The sulfoxide mayexist as one or more stereoisomers.

“Stereoisomer” and “stereoisomers” refer to compounds that have sameatomic connectivity but different atomic arrangement in space.Stereoisomers include cis-trans isomers, E and Z isomers, enantiomers,and diastereomers.

“Tautomer” refers to alternate forms of a molecule that differ in theposition of a proton, such as enol-keto and imine-enamine tautomers, orthe tautomeric forms of heteroaryl groups containing a —N═C(H)—NH— ringatom arrangement, such as pyrazoles, imidazoles, benzimidazoles,triazoles, and tetrazoles. A person of ordinary skill in the art wouldrecognize that other tautomeric ring atom arrangements are possible.

“Patient” refers to human and non-human animals, especially mammals.

“Pharmaceutically acceptable salt” refers to pharmaceutically acceptablesalts of a compound, which salts are derived from a variety of organicand inorganic counter ions well known in the art and include, by way ofexample only, sodium, potassium, calcium, magnesium, ammonium,tetraalkylammonium, and the like; and when the molecule contains a basicfunctionality, salts of organic or inorganic acids, such ashydrochloride, hydrobromide, tartrate, mesylate, acetate, maleate,oxalate, and the like.

“Prodrug” refers to a derivative of an active 4-pyrimidineamine compound(drug) that may require a transformation under the conditions of use,such as within the body, to release the active 2,4-pyrimidinediaminedrug. Prodrugs are frequently, but not necessarily, pharmacologicallyinactive until converted into the active drug. Prodrugs are typicallyobtained by masking one or more functional groups in an active2,4-pyrimidinediamine drug believed to be in part required for activitywith a progroup (defined below) to form a promoiety which undergoes atransformation, such as cleavage, under the specified conditions of useto release the functional group, and hence the active2,4-pyrimidinediamine drug. The cleavage of the promoiety may proceedspontaneously, such as by way of a hydrolysis reaction, or it can becatalyzed or induced by another agent, such as an enzyme, light, an acidor base, or a change of or exposure to a physical or environmentalparameter, such as temperature. The agent can be endogenous to theconditions of use, such as an enzyme present in the cells to which theprodrug is administered or the acidic conditions of the stomach, or itcan be supplied exogenously.

“Progroup” refers to a type of protecting group that, when used to maska functional group within an active 2,4-pyrimidinediamine drug to form apromoiety, converts the drug into a prodrug. Progroups are typicallyattached to the functional group of the drug via bonds that arecleavable under specified conditions of use. Thus, a progroup is thatportion of a promoiety that cleaves to release the functional groupunder the specified conditions of use. As a specific example, an amidepromoiety of the formula —NH—C(O)CH₃ comprises the progroup —C(O)CH₃.

“Pharmaceutically effective amount” and “therapeutically effectiveamount” refer to an amount of a compound sufficient to treat a specifieddisorder or disease or one or more of its symptoms and/or to prevent theoccurrence of the disease or disorder. In reference to tumorigenicproliferative disorders, a pharmaceutically or therapeutically effectiveamount comprises an amount sufficient to, among other things, cause thetumor to shrink or decrease the growth rate of the tumor.

“Solvate” refers to a complex formed by combination of solvent moleculeswith molecules or ions of the solute. The solvent can be an organiccompound, an inorganic compound, or a mixture of both. Some examples ofsolvents include, but are not limited to, methanol,N,N-dimethylformamide, tetrahydrofuran, dimethylsulfoxide, and water.

Unless indicated otherwise, the nomenclature of substituents that arenot explicitly defined herein are arrived at by naming the terminalportion of the functionality followed by the adjacent functionalitytoward the point of attachment. For example, the substituent“arylalkyloxycarbonyl” refers to the group (aryl)-(alkyl)-O—C(O)—.

It is understood that in all substituted groups defined above, polymersarrived at by defining substituents with further substituents tothemselves (e.g., substituted aryl having a substituted aryl group as asubstituent which is itself substituted with a substituted aryl group,which is further substituted by a substituted aryl group, etc.) are notintended for inclusion herein. In such cases, the maximum number of suchsubstitutions is three. For example, serial substitutions of substitutedaryl groups are limited to -substituted aryl-(substitutedaryl)-substituted aryl.

Similarly, it is understood that the above definitions are not intendedto include impermissible substitution patterns (e.g., methyl substitutedwith 5 fluoro groups). Such impermissible substitution patterns areeasily recognized by a person having ordinary skill in the art.

C. Compounds of the Invention

This invention provides novel 2,4-pyrimidinediamine compounds, prodrugsof the compounds, methods of making the compounds, and methods of usingthese compounds in the treatment of conditions in which targeting of theJAK pathway or inhibition of JAK kinases, particularly JAK3, aretherapeutically useful. These conditions include, but are not limitedto, debilitating and fatal diseases and disorders that affect bothchildren and adults. Examples of these conditions include oncologicaldiseases such as leukemia, including childhood leukemia and lymphoma;autoimmune conditions, such as transplant rejection; and the otherconditions described herein. Given the severity of and suffering causedby these conditions, it is vital that new treatments are developed totreat these conditions.

An aspect of the present invention provides a compound of the formula I:

a solvate, prodrug or pharmaceutically acceptable salt thereof, wherein:

-   -   ring A is aryl, or heteroaryl;    -   ring B is aryl, heteroaryl, cycloalkyl, or heterocyclic;    -   p is 0, 1, 2 or 3 when ring A is monocyclic or p is 0, 1, 2, 3,        4, or 5 when ring A contains multiple rings;    -   q is 0, 1, 2 or 3 when ring B is monocyclic or q is 0, 1, 2, 3,        4, or 5 when ring B contains multiple rings;    -   X is selected from the group consisting of alkyl, substituted        alkyl, hydroxy, alkoxy, substituted alkoxy, amino, substituted        amino, carboxyl, carboxyl ester, cyano, halo, nitro, alkenyl,        substituted alkenyl, alkynyl, and substituted alkynyl;    -   W is —SO₂N(R⁴)R⁵, -alk-SO₂N(R⁴)R⁵, —N(R⁴)SO₂R⁵, or        -alk-N(R⁴)SO₂R⁵;    -   -alk- is selected from the group consisting of straight or        branched chain C₁₋₆ alkylene group, and straight or branched        chain substituted C₁₋₆ alkylene group;    -   R¹ is hydrogen or C₁₋₃ alkyl;    -   each R² independently is selected from the group consisting of        alkyl, substituted alkyl, alkoxy, substituted alkoxy, alkenyl,        substituted alkenyl, alkynyl, substituted alkynyl, cycloalkenyl,        substituted cycloalkenyl, alkynyloxy, amino, substituted amino,        aryl, substituted aryl, aryloxy, substituted aryloxy, cyano,        cycloalkyl, substituted cycloalkyl, cycloalkoxy, substituted        cycloalkoxy, heteroaryl, substituted heteroaryl, heteroaryloxy,        substituted heteroaryloxy, heterocyclic, substituted        heterocyclic, heterocyclyloxy, substituted heterocyclyloxy,        aminocarbonyl, aminocarbonyloxy, carboxyl, carboxyl ester,        (carboxyl ester)oxy, nitro, halo, and oxo, wherein if R² is oxo,        then the oxo substituent is attached to a nonaromatic portion of        ring A; or        -   R⁴ and one of R² together with the intervening atoms bound            thereto form a heterocyclic or a substituted heterocyclic            fused to ring A; or        -   R⁵ and one of R² together with the intervening atoms bound            thereto form a heterocyclic or a substituted heterocyclic            fused to ring A; or    -   each R³ independently is selected from the group consisting of        alkyl, substituted alkyl, alkoxy, substituted alkoxy, alkenyl,        substituted alkenyl, alkynyl, substituted alkynyl, alkynyloxy,        amino, substituted amino, aryl, substituted aryl, aryloxy,        substituted aryloxy, cyano, cycloalkyl, substituted cycloalkyl,        cycloalkoxy, substituted cycloalkoxy, heteroaryl, substituted        heteroaryl, heteroaryloxy, substituted heteroaryloxy,        heterocyclic, substituted heterocyclic, heterocyclyloxy,        substituted heterocyclyloxy, aminocarbonyl, aminocarbonyloxy,        carboxyl, carboxyl ester, (carboxyl ester)oxy, nitro, and halo;        or    -   R⁴ is selected from the group consisting of hydrogen, alkyl,        substituted alkyl, cycloalkyl, substituted cycloalkyl,        heterocyclic, substituted heterocyclic, aryl, substituted aryl,        heteroaryl, substituted heteroaryl, acyl and M⁺, wherein M⁺ is a        counterion selected from the group consisting of K⁺, Na⁺, Li⁺        and ⁺N(R⁸)₄, wherein R⁸ is hydrogen or alkyl, and the nitrogen        of —SO₂N(R⁴)R⁵ or —N(R⁴)SO₂R⁵ is N⁻;    -   R⁵ is selected from the group consisting of hydrogen, alkyl,        substituted alkyl, amino, alkylamino, dialkylamino,        cycloalkylamino, cycloalkyl, substituted cycloalkyl,        heterocyclic, substituted heterocyclic, aryl, substituted aryl,        heteroaryl, substituted heteroaryl, and acyl; or    -   R⁴ and R⁵ together with the intervening atom or atoms bound        thereto form a heterocyclic or a substituted heterocyclic group.

In a preferred implementation, when W is —SO₂N(R⁴)R⁵, then W is notbound to an atom adjacent to the atom of ring A that is bound to N4 ofthe pyrimidine in formula I. Preferably, when W is —N(R⁴)SO₂R⁵, then Ais not chromanyl. Also preferably, when W is —SO₂N(R⁴)R⁵ and X is haloor alkyl, then R³ is not methoxy. Still preferably, when W is—SO₂N(R⁴)R⁵ and X is bromo, then R³ is not alkoxy, substituted alkoxy orhalo.

In a preferred implementation, when W is —SO₂N(R⁴)R⁵, then W is notbound to an atom adjacent to the atom of ring A that is bound to N4 ofthe pyrimidine in formula I, which is illustrated as follows:

In this implementation, A is phenyl. Therefore, W will not besubstituted on an atom shown by *, ortho to the carbon attached to N4 ofthe pyrimidinediamine core. Similarly, when ring A is an aromatic moietyother than phenyl, W is not substituted on an atom adjacent to the atomof ring A that is attached to N4 on the prymidinediamine core.

In other implementations, R⁴ is selected from a variety of moietiesincluding a counterion, designated as M. Although M⁺ is preferably amonovalent cation, such as, K⁺, Na⁺, or Li⁺, it can however also be adivalent cation with appropriate counterions, for example, two of theparent drug mono anion, one of parent/one of other counter anion, onedivalent parent anion with one divalent cation, etc.

In one implementation, A is aryl, preferably phenyl. In anotherimplementation, p is zero and (ring A-W) is:

In a preferred implementation, B is aryl or heteroaryl. More preferably,B—(R³)_(q) is selected from the group consisting of:

wherein Q is carbon or nitrogen.

In a preferred implementation, the compound is represented by formulaII:

a solvate, prodrug or pharmaceutically acceptable salt thereof, whereinR¹, R², R³, R⁴, R⁵, X, p and q are as defined for compound of formula I,and -alk- is a straight chain C₁₋₆ alkylene group.

In one implementation, R¹ is selected from the group consisting ofhydrogen or C₁₋₃ alkyl; R² is selected from the group consisting ofalkyl, or substituted alkyl, alkoxy, substituted alkoxy, and halo; R³ isselected from the group consisting of alkyl, substituted alkyl, alkoxy,substituted alkoxy, halo, cyano, cycloalkyl, substituted cycloalkyl,heterocyclic, substituted heterocyclic, aminocarbonyl, heteroaryl,substituted heteroaryl, aryl, and substituted aryl; X is alkyl,substituted alkyl, fluoro, chloro, bromo, amino, or substituted amino;-alk- is methylene or ethylene; R⁴ is hydrogen, alkyl, substitutedalkyl, cycloalkyl, or substituted cycloalkyl; and R⁵ is hydrogen, alkyl,substituted alkyl, cycloalkyl, or substituted cycloalkyl.

In one preferred implementation, R¹ is hydrogen. In one preferredimplementation, R³ is methyl, methoxy, or substituted methoxy. In onepreferred implementation, R⁴ and R⁵ independently are selected from thegroup consisting of hydrogen, alkyl, substituted alkyl substituted withalkynyl, and cyclopropyl. In one preferred implementation, p is 0; and qis 1, 2 or 3.

In one implementation, the compound is represented by formula IIa:

a solvate, prodrug or pharmaceutically acceptable salt thereof, whereinR¹, R², R³, R⁴, R⁵, X, p and q are as defined for compound of formula I,wherein —SO₂N(R⁴)R⁵ is attached to the phenyl ring at the 3-, 4-, or -5position; and provided that

-   -   a) when X is halo or alkyl, then R³ is not methoxy; and    -   b) when X is bromo, then R³ is not alkoxy, substituted alkoxy or        halo.

In one implementation, R¹ is hydrogen or C₁₋₂ alkyl; R² is alkyl; R³ isselected from the group consisting of alkyl, substituted alkyl, alkoxy,substituted alkoxy; X is alkyl, substituted alkyl, fluoro, chloro,bromo, amino, or substituted amino; R⁴ is hydrogen, alkyl, substitutedalkyl, cyclopropyl, or substituted cyclopropyl; and R⁵ is hydrogen,alkyl, substituted alkyl, cyclopropyl, or substituted cyclopropyl.

In one preferred implementation, R¹ is hydrogen or methyl. In onepreferred implementation, R² is methyl. In one preferred implementation,R³ is methyl, methoxy, or substituted methoxy substituted with alkynyl,aminocarbonyl, or heteroaryl. In one preferred implementation, X ismethyl, fluoro, trifluoromethyl, or amino. In one preferredimplementation, -alk- is methylene. In one preferred implementation, R⁴and R⁵ independently are selected from the group consisting of hydrogen,alkyl, substituted alkyl substituted with alkynyl, and cyclopropyl. Inone preferred implementation, p is 0 or 1; and q is 1, 2 or 3.

In another implementation, the compound is represented by formula III:

a solvate, prodrug or pharmaceutically acceptable salt thereof, whereinR², R³, X, p and q are as defined for compound of formula I; W is—N(R⁴)SO₂R⁵, or -alk-N(R⁴)SO₂R⁵ wherein R⁴ and R⁵ are as defined forcompound of formula I; and -alk- is a straight chain C₁₋₆ alkylene.

In one implementation, p is 0 or 1; and q is 1, 2, or 3; R³ is selectedfrom the group consisting of alkyl, substituted alkyl, alkoxy,substituted alkoxy, halo, cyano, cycloalkyl, substituted cycloalkyl,heterocyclic, substituted heterocyclic, aminocarbonyl, heteroaryl,substituted heteroaryl, aryl, and substituted aryl; X is alkyl,substituted alkyl, fluoro, chloro, or bromo; -alk- is methylene orethylene; and R⁴ and R⁵ independently are selected from the groupconsisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, andsubstituted cycloalkyl.

In one preferred implementation, R³ is selected from the groupconsisting of alkyl, substituted alkyl, alkoxy, substituted alkoxy,halo, cyano, heterocyclic, substituted heterocyclic, aminocarbonyl,heteroaryl, and substituted heteroaryl. In one preferred implementation,X is methyl, fluoro, or chloro. In one preferred implementation, -alk-is methylene. In one preferred implementation, R⁴ and R⁵ independentlyare selected from the group consisting of hydrogen, alkyl, andcyclopropyl. In one preferred implementation, p is 0. In one preferredimplementation, —N(R⁴)SO₂R⁵ is —N(H)SO₂-cyclopropyl.

In one preferred implementation, this invention provides a compoundrepresented by formula IIIa, a solvate, prodrug, or pharmaceuticallyacceptable salt thereof:

wherein R², R³, R⁴, R⁵, X, p and q are as defined for compound offormula I, and -alk- is a straight chain C₁₋₆ alkylene.

In one implementation, the compound is represented by formula IV:

a solvate, prodrug or pharmaceutically acceptable salt thereof, whereinQ is carbon or nitrogen, and R³, R⁴, R⁵, -alk-, X, and q are as definedfor compound of formula I.

In one preferred implementation, Q is carbon. In one preferredimplementation, Q is nitrogen. In one implementation, X is alkyl,substituted alkyl, fluoro, chloro, or bromo; -alk- is methylene; R³ isselected from the group consisting of alkyl, substituted alkyl,heterocyclic, substituted heterocyclic, and aminocarbonyl; and R⁴ and R⁵independently are selected from the group consisting of hydrogen, alkyl,substituted alkyl, cycloalkyl, and substituted cycloalkyl. In onepreferred implementation, X is methyl, fluoro, or chloro. In onepreferred implementation, R⁴ and R⁵ independently are selected from thegroup consisting of hydrogen, alkyl, and cyclopropyl.

In one implementation, the compound is represented by formula V:

a solvate, prodrug or pharmaceutically acceptable salt thereof, whereinQ is carbon, or nitrogen, and wherein R³, R⁴, R⁵, X, -alk-, and q are asdefined for compound of formula I.

In one preferred implementation, Q is carbon. In one preferredimplementation, Q is nitrogen. In one implementation, X is alkyl,substituted alkyl, or halo; Q is nitrogen; -alk- is methylene; R³ isselected from the group consisting of alkyl, substituted alkyl, alkoxy,substituted alkoxy, halo, cycloalkyl, substituted cycloalkyl,heterocyclic, substituted heterocyclic, aminocarbonyl, heteroaryl,substituted heteroaryl, aryl, and substituted aryl; and R⁴ and R⁵independently are selected from the group consisting of hydrogen, alkyl,substituted alkyl, cycloalkyl, and substituted cycloalkyl. In onepreferred implementation, X is methyl. In one preferred implementation,R³ is selected from the group consisting of alkyl, substituted alkyl,heterocyclic, substituted heterocyclic, aminocarbonyl, heteroaryl, andsubstituted heteroaryl. In one preferred implementation, R⁴ and R⁵independently are selected from the group consisting of hydrogen, alkyl,and cyclopropyl.

In yet another implementation, this invention provides a compound offormula VI, a solvate, prodrug, or pharmaceutically acceptable saltthereof:

wherein X, R³ and R⁵ are as defined above. In a preferredimplementation, X is alkyl, R³ is alkyl, alkoxy, halo, heterocyclic orheteroaryl and R⁵ is alkyl or cycloalkyl.

In yet another implementation, this invention provides a compound offormula VII, a solvate, prodrug, or pharmaceutically acceptable saltthereof:

wherein X, Z, R³ and R⁵ are as defined above. In a preferredimplementation, X is halo, Z is CH, R⁵ is alkyl and R³ is heterocyclic,alkyl or alkoxy.

In yet another implementation, this invention provides a compound offormula VIII, a solvate, prodrug, or pharmaceutically acceptable saltthereof:

wherein X, Z, and R³ are as defined above. In a preferredimplementation, X is alkyl or halo and R³ is alkyl, alkoxy orheterocyclic.

The compounds of this invention also include:

or a solvate, prodrug or pharmaceutically acceptable salt thereof.In one implementation, the compound is selected from the groupconsisting of:

-   I-1:    5-Fluoro-N4-[3-(prop-2-ynylaminosulfonyl)phenyl]-N2-(3,4,5-trimethoxyphenyl)-2,4-pyrimidinediamine;-   I-2:    N4-(3-Aminosulfonyl-4-methylphenyl)-5-methyl-N2-[4-(prop-2-ynyloxy)phenyl]-2,4-pyrimidinediamine;-   I-3:    N4-(3-Aminosulfonyl-4-methylphenyl)-N2-[4-(prop-2-ynyloxy)phenyl]-5-trifluoromethyl-2,4-pyrimidinediamine;-   I-4:    N2-(3,5-Dimethyl-4-methoxyphenyl)-5-fluoro-N4-[3-(prop-2-ynylaminosulfonyl)phenyl]-2,4-pyrimidinediamine;-   I-5:    N2-(3,5-Dimethyl-4-methoxyphenyl)-5-fluoro-N4-[4-(prop-2-ynylaminosulfonyl)phenyl]-2,4-pyrimidinediamine;-   I-6:    5-Amino-N4-(4-aminosulfonylphenyl)-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine;-   I-7:    5-Amino-N4-(3-aminosulfonylphenyl)-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine;-   I-8:    5-Amino-N4-(3-aminosulfonylphenyl)-N2-(4-methoxyphenyl)-N2-methyl-2,4-pyrimidinediamine;-   I-9:    5-Amino-N4-(4-aminosulfonylphenyl)-N2-(4-methoxyphenyl)-N2-methyl-2,4-pyrimidinediamine;-   II-1:    N4-(4-cyclopropylsulfonylaminomethyl)phenyl-5-fluoro-N2-(3,4,5-trimethoxy)phenyl-2,4-pyrimidinediamine;-   I-10:    5-Amino-N4-(3-aminosulfonylphenyl)-N2-(3-methoxyphenyl)-N2-methyl-2,4-pyrimidinediamine;-   I-11:    5-Amino-N4-(4-aminosulfonylphenyl)-N2-(3-methoxyphenyl)-N2-methyl-2,4-pyrimidinediamine;-   I-12:    N4-(3-Aminosulfonylphenyl)-N2-[4-(2-pyridinyl)methyleneoxyphenyl]-5-trifluoromethyl-2,4-pyrimidinediamine;-   I-13:    N4-[4-N-(Cyclopropyl)aminosulfonylphenyl]-N2-[4-(3-pyridinyl)methyleneoxyphenyl]-5-trifluoromethyl-2,4-pyrimidinediamine;-   I-14:    N4-[(3-(1,1-Dimethylamino)sulfonyl)phenyl]-5-methyl-N2-[4-(4-methyl-1-piperazinyl)phenyl]-2,4-pyrimidinediamine;-   I-15:    5-Chloro-N4-[3-(N-tert-butylsulfonyl)phenyl]-N2-[3,4,5-trimethoxyphenyl]-2,4-pyrimidinediamine;-   I-16:    5-Chloro-N4-[3-(N-tert-butylsulfonyl)phenyl]-N2-[3,4-trimethyl-4-methoxyphenyl]-2,4-pyrimidinediamine;-   I-17:    5-Chloro-N4-[3-(N-tert-butylsulfonyl)phenyl]-N2-[4-(N-methylpiperidin-4-yl)phenyl]-2,4-pyrimidinediamine;-   I-18:    5-Bromo-N4-[3-(N-tert-butylsulfonyl)phenyl]-N2-[4-(4-methylpiperazine)-phenyl]-2,4-pyrimidinediamine;-   I-19:    N4-[3-(N-tert-butylsulfonyl)phenyl]-N2-[4-(4-methylpiperazine)-phenyl]-2,4-pyrimidinediamine;-   I-20:    5-Methyl-N4-[3-(N-tert-butylsulfonyl)phenyl]-N2-[3,5-dimethyl-4-(2-(1-morpholino)ethoxyphenyl]-2,4-pyrimidinediamine;-   I-21:    5-Chloro-N4-[3-(N-tert-butylsulfonyl)phenyl]-N2-[3,5-dimethyl-4-(2-(1-morpholino)ethoxyphenyl]-2,4-pyrimidinediamine;-   I-22:    5-Chloro-N4-[(3-(1,1-dimethylethylamino)sulfonyl)phenyl]-N2-[3-methyl-4-[(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]phenyl]-2,4-pyrimidinediamine;-   II-2:    N4-(4-cyclopropylsulfonylaminomethyl)phenyl-N2-(3,4-difluoro)phenyl-5-fluoro-2,4-pyrimidinediamine;-   II-3:    N2-(3-chloro-4-methoxy)phenyl-N4-(4-cyclopropylsulfonylaminomethyl)phenyl-5-fluoro-2,4-pyrimidinediamine;-   II-4:    N4-(4-cyclopropylsulfonylaminomethyl)phenyl-N2-(3,5-dimethyl)phenyl-5-fluoro-2,4-pyrimidinediamine;-   II-5:    N2-(3-chloro-4-cyano)phenyl-N4-(4-cyclopropylsulfonylaminomethyl)phenyl-5-fluoro-2,4-pyrimidinediamine;-   II-6:    N4-(4-cyclopropylsulfonylaminomethyl)phenyl-N2-[4-(4-ethylpiperazino)-3-methyl]phenyl-5-fluoro-2,4-pyrimidinediamine;-   II-7:    N4-(4-cyclopropylsulfonylaminomethyl)phenyl-N2-(3,5-dimethyl)phenyl-5-methyl-2,4-pyrimidinediamine;-   II-8:    N4-(4-cyclopropylsulfonylaminomethyl)phenyl-N2-[4-(4-ethylpiperazino)-3-methyl]phenyl-5-methyl-2,4-pyrimidinediamine;-   II-9:    N4-(4-cyclopropylsulfonylaminomethyl)phenyl-5-methyl-N2-(3,4,5-trimethoxy)phenyl-2,4-pyrimidinediamine;-   II-10:    N2-(3-chloro-4-methoxy)phenyl-N4-(4-cyclopropylsulfonylaminomethyl)phenyl-5-methyl-2,4-pyrimidinediamine;-   II-11:    N4-(3-cyclopropylsulfonylaminomethyl)phenyl-N2-(3,5-dimethyl)phenyl-5-methyl-2,4-pyrimidinediamine;-   II-12:    N4-(3-cyclopropylsulfonylaminomethyl)phenyl-N2-[4-(4-ethylpiperazino)-3-methyl]phenyl-5-methyl-2,4-pyrimidinediamine;-   II-13:    N4-(3-cyclopropylsulfonylaminomethyl)phenyl-5-methyl-N2-(3,4,5-trimethoxy)phenyl-2,4-pyrimidinediamine;-   II-14:    N2-(3-chloro-4-methoxy)phenyl-N4-(3-cyclopropylsulfonylaminomethyl)phenyl-5-methyl-2,4-pyrimidinediamine;-   II-15:    N2-(4-aminocarbonyl)phenyl-N4-(4-cyclopropylsulfonylaminomethyl)phenyl-5-fluoro-2,4-pyrimidinediamine;-   II-16:    N2-(3-aminocarbonyl)phenyl-N4-(4-cyclopropylsulfonylaminomethyl)phenyl-5-fluoro-2,4-pyrimidinediamine;-   II-17:    N2-(4-aminocarbonyl)phenyl-N4-(3-chloro-4-cyclopropylsulfonylaminomethyl)phenyl-5-methyl-2,4-pyrimidinediamine;-   II-18:    N2-(3-aminocarbonyl)phenyl-N4-(3-chloro-4-cyclopropylsulfonylaminomethyl)phenyl-5-methyl-2,4-pyrimidinediamine;-   II-19:    N2-(4-aminocarbonyl)phenyl-N4-[4-(N-cyclopropylsulfonyl-N-methyl)aminomethyl]phenyl-5-methyl-2,4-pyrimidinediamine;-   II-20:    N2-(3-aminocarbonyl)phenyl-N4-[4-(N-cyclopropylsulfonyl-N-methyl)aminomethyl]phenyl-5-methyl-2,4-pyrimidinediamine;-   II-21:    N2-(4-aminocarbonyl)phenyl-N4-[3-(N-cyclopropylsulfonyl-N-methyl)aminomethyl]phenyl-5-methyl-2,4-pyrimidinediamine;-   II-22:    N2-(3-aminocarbonyl)phenyl-N4-[3-(N-cyclopropylsulfonyl-N-methyl)aminomethyl]phenyl-5-methyl-2,4-pyrimidinediamine;-   II-23:    N2-(4-aminocarbonyl)phenyl-N4-(3-cyclopropylsulfonylaminomethyl)phenyl-5-methyl-2,4-pyrimidinediamine;-   II-24:    N2-(3-aminocarbonyl)phenyl-N4-(3-cyclopropylsulfonylaminomethyl)phenyl-5-methyl-2,4-pyrimidinediamine;-   II-25:    N2-(4-cyano)phenyl-N4-(3-cyclopropylsulfonylaminomethyl)phenyl-5-methyl-2,4-pyrimidinediamine;-   II-26:    N2-(3-cyano)phenyl-N4-(3-cyclopropylsulfonylaminomethyl)phenyl-5-methyl-2,4-pyrimidinediamine;-   II-27:    N2-(4-cyano)phenyl-N4-[4-(N-cyclopropylsulfonyl-N-methyl)aminomethyl]phenyl-5-methyl-2,4-pyrimidinediamine;-   II-28:    N2-(3-cyano)phenyl-N4-[4-(N-cyclopropylsulfonyl-N-methyl)aminomethyl]phenyl-5-methyl-2,4-pyrimidinediamine;-   II-29:    N2-(4-cyano)phenyl-N4-(4-cyclopropylsulfonylaminomethyl)phenyl-5-fluoro-2,4-pyrimidinediamine;-   II-30:    N2-(3-cyano)phenyl-N4-(4-cyclopropylsulfonylaminomethyl)phenyl-5-fluoro-2,4-pyrimidinediamine;-   II-31:    N2-(4-aminocarbonyl)phenyl-N4-(4-cyclopropylsulfonylaminomethyl)phenyl-5-methyl-2,4-pyrimidinediamine;-   II-32:    N2-(3-aminocarbonyl)phenyl-N4-(4-cyclopropylsulfonylaminomethyl)phenyl-5-methyl-2,4-pyrimidinediamine;-   II-33:    N2-(4-cyano)phenyl-N4-(4-cyclopropylsulfonylaminomethyl)phenyl-5-methyl-2,4-pyrimidinediamine;-   II-34:    N2-(3-cyano)phenyl-N4-(4-cyclopropylsulfonylaminomethyl)phenyl-5-methyl-2,4-pyrimidinediamine;-   II-35:    5-chloro-N2-(3-chloro-4-methoxy)phenyl-N4-(4-cyclopropylsulfonylaminomethyl)phenyl-2,4-pyrimidinediamine;-   II-36:    5-chloro-N4-(4-cyclopropylsulfonylaminomethyl)phenyl-N2-(3,5-dimethyl)phenyl-2,4-pyrimidinediamine;-   II-37:    N2-(4-aminocarbonyl)phenyl-5-chloro-N4-(4-cyclopropylsulfonylaminomethyl)phenyl-2,4-pyrimidinediamine;-   II-38:    N4-(3-chloro-4-cyclopropylsulfonylaminomethyl)phenyl-N2-(3,5-dimethyl)phenyl-5-methyl-2,4-pyrimidinediamine;-   II-39:    N4-[4-(N-cyclopropylsulfonyl-N-methyl)aminomethyl]phenyl-N2-(3,5-dimethyl)phenyl-5-methyl-2,4-pyrimidinediamine;-   II-40:    N4-[3-(N-cyclopropylsulfonyl-N-methyl)aminomethyl]phenyl-N2-(3,5-dimethyl)phenyl-5-methyl-2,4-pyrimidinediamine;-   II-41:    N4-(4-cyclopropylsulfonylaminomethyl)phenyl-N2-(3,5-dimethyl-4-methoxy)phenyl-5-fluoro-2,4-pyrimidinediamine;-   II-42:    N4-(4-cyclopropylsulfonylaminomethyl)phenyl-N2-(3,5-dimethyl-4-methoxy)phenyl-5-methyl-2,4-pyrimidinediamine;-   II-43:    5-chloro-N4-(4-cyclopropylsulfonylaminomethyl)phenyl-N2-(3,5-dimethyl-4-methoxy)phenyl-2,4-pyrimidinediamine;-   II-44:    N4-(3-cyclopropylsulfonylaminomethyl)phenyl-N2-(3,5-dimethyl-4-methoxy)phenyl-5-methyl-2,4-pyrimidinediamine;-   II-45:    5-Chloro-N4[4-(N-cyclopropylsulfonylamino)ethylphenyl]-N2-[4-phenyl    trifluoromethyl sulfone]-2,4-pyrimidinediamine;-   II-46:    5-Chloro-N4[4-(N-cyclopropylsulfonylamino)ethylphenyl]-N2-[4-(2,6-dimethyl-methoxy)phenyl]-2,4-pyrimidinediamine;-   II-47:    5-Chloro-N4[4-(N-cyclopropylsulfonylamino)ethylphenyl]-N2-[4-(2,6-dimethyl-ethoxy)phenyl]-2,4-pyrimidinediamine;-   II-48:    5-Chloro-N4[4-(N-cyclopropylsulfonylamino)ethylphenyl]-N2-[4-(2,6-dimethyl-isopropoxy)phenyl]-2,4-pyrimidinediamine;-   II-49:    5-Chloro-N4[4-(N-cyclopropylsulfonylamino)ethylphenyl]-N2-[4-(2,6-dimethyl-ethoxymorphlino)phenyl]-2,4-pyrimidinediamine);-   II-50:    5-Chloro-N4[4-(N-cyclopropylsulfonylamino)ethylphenyl]-N2-[4-(6-methoxy-2-methyl-methoxy)phenyl]-2,4-pyrimidinediamine;-   II-51:    5-Chloro-N4[4-(N-cyclopropylsulfonylamino)ethylphenyl]-N2-[4-(4-methylpiperazino)phenyl]-2,4-pyrimidinediamine;-   II-52:    5-Chloro-N4[4-(N-cyclopropylsulfonylamino)ethylphenyl]-N2-[4-(4-methylpiperazino)-2-methylphenyl]-2,4-pyrimidinediamine;-   II-53:    5-Chloro-N4[4-(N-cyclopropylsulfonylamino)ethylphenyl]-N2-[4-(4-methylpiperazino)pyrido]-2,4-pyrimidinediamine;-   II-54:    5-Chloro-N4[4-(N-cyclopropylsulfonylamino)ethylphenyl]-N2-[4-(4-propylpiperazino)-2-trifluoromethylphenyl]-2,4-pyrimidinediamine;-   II-55:    5-Chloro-N4[4-(N-cyclopropylsulfonylamino)ethylphenyl]-N2-[4-(4-methylsulfonylpiperazino)-2-trifluoromethylphenyl]-2,4-pyrimidinediamine;-   II-56:    5-Chloro-N4[4-(N-cyclopropylsulfonylamino)ethylphenyl]-N2-[4-(4-methylpiperazino)-2-fluorophenyl]-2,4-pyrimidinediamine;-   II-57:    5-Chloro-N4[4-(N-cyclopropylsulfonylamino)ethylphenyl]-N2-[4-(4-ethylpiperazino)-2-trifluoromethylphenyl]-2,4-pyrimidinediamine;-   II-58:    5-Chloro-N4[4-(N-cyclopropylsulfonylamino)ethylphenyl]-N2-[4-biphenyl]-2,4-pyrimidinediamine;-   II-59:    N4-[4-(N-cyclopropylsulfonylamino)ethylphenyl)]-5-methyl-N2-[4-trifluoromethylsulfonyl    phenyl]-2,4-pyrimidinediamine;-   II-60:    N-(4-(2-(4-(4-(bicyclo[2.2.1]heptan-2-yl)piperazin-1-yl)phenylamino)-5-methylpyrimidin-4-ylamino)benzyl)cyclopropanesulfonamide;-   II-61:    N-(4-(2-(4-(4-(bicyclo[2.2.1]heptan-2-yl)piperazin-1-yl)phenylamino)-5-chloropyrimidin-4-ylamino)benzyl)cyclopropanesulfonamide;-   II-62:    N4-[4-(N-cyclopropylsulfonylamino)ethylphenyl)]-5-methyl-N2-[4-(2,6-dimethyl)methoxyphenyl]-2,4-pyrimidinediamine;-   II-63:    N4-[4-(N-cyclopropylsulfonylamino)ethylphenyl)]-5-methyl-N2-[4-(2,6-dimethyl)ethoxyphenyl]-2,4-pyrimidinediamine;-   II-64:    N4-[4-(N-cyclopropylsulfonylamino)ethylphenyl)]-5-methyl-N2-[4-(2,6-dimethyl)    isopropoxyphenyl]-2,4-pyrimidinediamine;-   II-65:    N4-[4-(N-cyclopropylsulfonylamino)ethylphenyl)]-5-methyl-N2-[4-(2,6-dimethyl)ethoxymorpholino-phenyl]-2,4-pyrimidinediamine;-   II-66:    N4-[4-(N-cyclopropylsulfonylamino)ethylphenyl)]-5-methyl-N2-[4-(6-methoxy-2-methyl)methoxyphenyl]-2,4-pyrimidinediamine;-   II-67:    N4-[4-(N-cyclopropylsulfonylamino)ethylphenyl)]-5-methyl-N2-[4-(4-methylpiperazino)phenyl]-2,4-pyrimidinediamine;-   II-68:    N4-[4-(N-cyclopropylsulfonylamino)ethylphenyl)]-5-methyl-N2-[4-(4-methylpiperazino)-2-methylphenyl]-2,4-pyrimidinediamine;-   II-69:    N4-[4-(N-cyclopropylsulfonylamino)ethylphenyl)]-5-methyl-N2-[4-(4-methylpiperazino)pyrido]-2,4-pyrimidinediamine;-   II-70:    N4-[4-(N-cyclopropylsulfonylamino)ethylphenyl)]-5-methyl-N2-[4-(4-methylpiperazino)-2-trifluoromethylphenyl]-2,4-pyrimidinediamine;-   II-71:    N4-[4-(N-cyclopropylsulfonylamino)ethylphenyl)]-5-methyl-N2-[4-(4-propylpiperazino)-2-trifluoromethylphenyl]-2,4-pyrimidinediamine;-   II-72:    N4-[4-(N-cyclopropylsulfonylamino)ethylphenyl)]-5-methyl-N2-[4-(4-sulfonylmethyl-piperazino)-2-trifluoromethylphenyl]-2,4-pyrimidinediamine;-   II-73:    N4-[4-(N-cyclopropylsulfonylamino)ethylphenyl)]-5-methyl-N2-[4-(4-methylpiperazino)-2-fluorophenyl]-2,4-pyrimidinediamine;-   II-74:    N4-[4-(N-cyclopropylsulfonylamino)ethylphenyl)]-5-methyl-N2-[4-(4-ethylpiperazino)-2-trifluoromethylphenyl]-2,4-pyrimidinediamine;-   II-75:    N4-[4-(N-cyclopropylsulfonylamino)ethylphenyl)]-5-methyl-N2-[4-biphenyl]-2,4-pyrimidinediamine;-   II-76:    N-(3-(2-(4-(4-(bicyclo[2.2.1]heptan-2-yl)piperazin-1-yl)phenylamino)-5-chloropyrimidin-4-ylamino)-5-methylbenzyl)cyclopropanesulfonamide;-   II-77:    N-(3-(2-(4-(4-(bicyclo[2.2.1]heptan-2-yl)piperazin-1-yl)phenylamino)-5-methylpyrimidin-4-ylamino)-5-methylbenzyl)cyclopropanesulfonamide;-   II-78:    N-(4-(2-(4-(4-(bicyclo[2.2.1]heptan-2-yl)piperazin-1-yl)-3-fluorophenylamino)-5-methylpyrimidin-4-ylamino)benzyl)cyclopropanesulfonamide;-   II-79:    N-(4-(2-(4-(4-(bicyclo[2.2.1]heptan-2-yl)piperazin-1-yl)-3-fluorophenylamino)-5-chloropyrimidin-4-ylamino)benzyl)cyclopropanesulfonamide;-   II-80:    5-Chloro-N2-(3-chloro-4-methoxy-5-methylphenyl]-N4-[4-(N-cyclopropylsulfonylamino)methylphenyl]-2,4-pyrimidinediamine;-   II-81:    N4-[4-(N-Cyclopropylsulfonylamino)methylphenyl]-N2-(3,5-dimethyl-4-methoxyphenyl)-5-ethyl-2,4-pyrimidinediamine;-   II-82:    N4-[4-(N-Cyclopropylsulfonylamino)methylphenyl]-N2-(3,4-dimethoxy-5-methylphenyl)-5-ethyl-2,4-pyrimidinediamine;-   II-83:    N2-(3-Chloro-4-methoxy-5-methylphenyl)-N4-[4-(N-cyclopropylsulfonylamino)methylphenyl]-5-ethyl-2,4-pyrimidinediamine;-   II-84:    N4-[4-(N-Cyclopropylsulfonylamino)methylphenyl]-N2-(3,5-dichloro-4-methoxyphenyl)-5-ethyl-2,4-pyrimidinediamine;-   II-85:    N4-[4-(N-Cyclopropylsulfonylamino)methylphenyl]-5-ethyl-N2-(3-,4,5-trimethoxylphenyl)-2,4-pyrimidinediamine;-   II-86:    N4-[4-(N-Cyclopropylsulfonylamino)methylphenyl]-5-ethyl-N2-[4-(4-methyl-1-piperazinyl)phenyl]-2,4-pyrimidinediamine;-   II-87:    N4-[4-(N-Cyclopropylsulfonylamino)methylphenyl]-N2-[4-(4,4-difluoro-1-piperidinyl)phenyl]-5-ethyl-2,4-pyrimidinediamine;-   II-88:    N4-[4-(N-Cyclopropylsulfonylamino)methylphenyl]-5-ethyl-N2-[4-(1-methyl-4-piperidinyl)pheny]-2,4-pyrimidinediamine;-   II-89:    N4-[4-(N-Cyclopropylsulfonylamino)methylphenyl]-5-ethyl-N2-[4-(4-ethyl-1-piperazinyl)phenyl]-2,4-pyrimidinediamine;-   II-90:    5-Chloro-N2-(3,5-dimethyl-5-methoxyphenyl)-N4-[(4-(dimethylamino)sulfonylamino)methylphenyl]-2,4-pyrimidinediamine;-   II-91:    5-Chloro-N2-(3,4-dimethoxy-5-methylphenyl)-N4-[(4-(dimethylamino)sulfonylamino)methylphenyl]-2,4-pyrimidinediamine;-   II-92:    5-Chloro-N2-(3-chloro-4,5-dimethoxyphenyl)-N4-[(4-(dimethylamino)sulfonylamino)methylphenyl]-2,4-pyrimidinediamine;-   II-93:    5-Chloro-N2-(3-chloro-4-methoxy-5-methylphenyl)-N4-[(4-(dimethylamino)sulfonylamino)methylphenyl]-2,4-pyrimidinediamine;-   II-94:    5-Chloro-N2-[3,5-dichloro-4-methoxyphenyl]-N4-[(4-(dimethylamino)sulfonylamino)methylphenyl]-2,4-pyrimidinediamine;-   II-95:    5-Chloro-N4-[(4-(dimethylamino)sulfonylamino)methylphenyl]-N2-[3,4,5-trimethoxyphenyl)-2,4-pyrimidinediamine;-   II-96:    5-Chloro-N4-[(4-(dimethylamino)sulfonylamino)methylphenyl]-N2-[4-(4-methyl-1-piperazinyl)phenyl]-2,4-pyrimidinediamine;-   II-97:    5-Chloro-N4-[(4-(dimethylamino)sulfonylamino)methylphenyl]-N2-[4-(4,4-difluoro-1-piperidinyl)phenyl]-2,4-pyrimidinediamine;-   II-98:    5-Chloro-N4-[(4-(dimethylamino)sulfonylamino)methylphenyl]-N2-[4-(1-methyl-4-piperidinyl)pheny]-2,4-pyrimidinediamine;-   II-99:    4-[(4-(Dimethylamino)sulfonylamino)methylphenyl]-N2-(3,5-dimethyl-4-methoxyphenyl)-5-methyl-2,4-pyrimidinediamine;-   II-100:    4-[(4-(Dimethylamino)sulfonylamino)methylphenyl]-N2-(3,4-dimethoxy-5-methylphenyl)-5-methyl-2,4-pyrimidinediamine;-   II-101:    5-Methyl-N2-(3-chloro-4-methoxy-5-methylphenyl)-N4-[(4-(dimethylamino)sulfonylamino)methylphenyl]-2,4-pyrimidinediamine;-   II-102:    5-methyl-N2-[3,5-dichloro-4-methoxyphenyl]-N4-[(4-(dimethylamino)sulfonylamino)methylphenyl]-2,4-pyrimidinediamine;-   II-103:    N4-[(4-(Dimethylamino)sulfonylamino)methylphenyl]-5-methyl-N2-(3,4,5-trimethoxyphenyl)-2,4-pyrimidinediamine;-   II-104:    N4-[(4-(Dimethylamino)sulfonylamino)methylphenyl]-5-methyl-N2-[4-(4-methyl-1-piperazinyl)phenyl]-2,4-pyrimidinediamine;-   II-105:    N4-[(4-(Dimethylamino)sulfonylamino)methylphenyl]-N2-[4-(4,4-difluoro-1-piperidinyl)phenyl]-5-methyl-2,4-pyrimidinediamine;-   II-106:    N4-[(4-(Dimethylamino)sulfonylamino)methylphenyl]-5-methyl-N2-[4-(1-methyl-4-piperidinyl)pheny]-2,4-pyrimidinediamine;-   II-107:    N4-[(4-(Dimethylamino)sulfonylamino)methylphenyl]-5-methyl-N2-[4-(4-ethyl-1-piperazinyl)phenyl]-2,4-pyrimidinediamine;-   II-108:    5-chloro-N2-(3,5-Dimethyl-4-methoxyphenyl)-N4-[(4-(ethylamino)sulfonylamino)methylphenyl]-2,4-pyrimidinediamine;-   II-109:    5-Chloro-4-[(4-(ethylamino)sulfonylamino)methylphenyl]-N2-(3,4-dimethoxy-5-methylphenyl)-2,4-pyrimidinediamine;-   II-110:    5-Chloro-N2-(3-chloro-4-methoxy-5-methylphenyl)-N4-[(4-(ethylamino)sulfonylamino)methylphenyl]-2,4-pyrimidinediamine;-   II-111:    5-Chloro-N2-[3,5-dichloro-4-methoxyphenyl]-N4-[(4-(ethylamino)sulfonylamino)methylphenyl]-2,4-pyrimidinediamine;-   II-112:    5-Chloro-N4-[(4-(ethylamino)sulfonylamino)methylphenyl]-N2-(3,4,5-trimethoxyphenyl)-2,4-pyrimidinediamine;-   II-113:    5-Chloro-N2-(3-chloro-4,5-dimethoxyphenyl)-N4-[(4-(ethylamino)sulfonylamino)methylphenyl]-2,4-pyrimidinediamine;-   II-114:    5-Chloro-N4-[(4-(ethylamino)sulfonylamino)methylphenyl]-N2-[4-(4-methyl-1-piperazinyl)phenyl]-2,4-pyrimidinediamine;-   II-115:    5-chloro-N4-[(4-(ethylamino)sulfonylamino)methylphenyl]-N2-[4-(1-methyl-4-piperidinyl)pheny]-2,4-pyrimidinediamine;-   II-116:    N2-(3,5-Dimethyl-4-methoxyphenyl)-N4-[(4-(ethylamino)sulfonylamino)methylphenyl]-5-methyl-2,4-pyrimidinediamine;-   II-117:    N2-(3,4-Dimethoxy-5-methylphenyl)-N4-[(4-(ethylamino)sulfonylamino)methylphenyl]-5-methyl-2,4-pyrimidinediamine;-   II-118:    N2-(3-Chloro-4-methoxy-5-methylphenyl)-N4-[(4-(ethylamino)sulfonylamino)methylphenyl]-5-methyl-2,4-pyrimidinediamine;-   II-119:    N2-[3,5-Dichloro-4-methoxyphenyl]-N4-[(4-(ethylamino)sulfonylamino)methylphenyl]-5-methyl-2,4-pyrimidinediamine;-   II-120:    N4-[(4-(Ethylamino)sulfonylamino)methylphenyl]-5-methyl-N2-(3,4,5-trimethoxyphenyl)-2,4-pyrimidinediamine;-   II-121:    N2-(3-Chloro-4,5-dimethoxyphenyl)-N4-[(4-(ethylamino)sulfonylamino)methylphenyl]-5-methyl-2,4-pyrimidinediamine;-   II-122:    N4-[(4-(Ethylamino)sulfonylamino)methylphenyl]-5-methyl-N2-[4-(4-methyl-1-piperazinyl)phenyl]-2,4-pyrimidinediamine;-   II-123:    N2-[4-(4,4-Difluoro-1-piperidinyl)phenyl]-N4-[(4-(ethylamino)sulfonylamino)methylphenyl]-5-methyl-2,4-pyrimidinediamine;-   II-124:    N4-[(4-(Ethylamino)sulfonylamino)methylphenyl]-5-methyl-N2-[4-(1-methyl-4-piperidinyl)pheny]-2,4-pyrimidinediamine;-   II-125:    N4-[(4-(ethylamino)sulfonylamino)methylphenyl]-N2-[4-(4-ethyl-1-piperazinyl)phenyl]-5-methyl-2,4-pyrimidinediamine;-   II-126:    N4-[4-(N-Cyclopropylsulfonylamino)methylphenyl]-N2-(3,5-dimethyl-4-methoxyphenyl)-5-trifluoromethyl-2,4-pyrimidinediamine;-   II-127:    N4-[4-(N-Cyclopropylsulfonylamino)methylphenyl]-N2-[4-(4-methyl-1-piperazinyl)phenyl]-5-trifluoromethyl-2,4-pyrimidinediamine;-   II-128:    N4-[4-(N-Cyclopropylsulfonylamino)methylphenyl]-N2-[3-methyl-4-(4-methyl-1-piperazinyl)phenyl]-5-trifluoromethyl-2,4-pyrimidinediamine;-   II-129:    5-Chloro-N2-(3,5-dimethyl-4-methoxyphenyl)-N4-[(3-(ethylamino)sulfonylamino)methylphenyl]-2,4-pyrimidinediamine;-   II-130:    5-Chloro-N2-(3,5-dimethyl-4-ethoxyphenyl)-N4-[(3-(ethylamino)sulfonylamino)methylphenyl]-2,4-pyrimidinediamine;-   II-131:    5-Chloro-N4-[(3-(ethylamino)sulfonylamino)methylphenyl]-N2-[4-(4-methyl-1-piperazinyl)phenyl]-2,4-pyrimidinediamine;-   II-132:    5-Chloro-N4-[(3-(ethylamino)sulfonylamino)methylphenyl]-N2-[3-methyl-4-(4-methyl-1-piperazinyl)phenyl]-2,4-pyrimidinediamine;-   II-133:    N2-(3,5-Dimethyl-4-methoxyphenyl)-N4-[(3-(ethylamino)sulfonylamino)methylphenyl]-5-methyl-2,4-pyrimidinediamine;-   II-134:    N2-(3,5-Dimethyl-4-ethoxyphenyl)-N4-[(3-(ethylamino)sulfonylamino)methylphenyl]-5-methyl-2,4-pyrimidinediamine;-   II-135:    N4-[(3-(Ethylamino)sulfonylamino)methylphenyl]-5-methyl-N2-[4-(4-methyl-1-piperazinyl)phenyl]-2,4-pyrimidinediamine;-   II-136:    N4-[3-((Ethylamino)sulfonylamino)methylphenyl]-5-methyl-N2-[3-methyl-4-(4-methyl-1-piperazinyl)phenyl]-2,4-pyrimidinediamine;-   II-137:    N2-(3,5-Dimethyl-4-methoxyphenyl)-N4-[(3-(ethylamino)sulfonylamino)methylphenyl]-5-fluoro-2,4-pyrimidinediamine;-   II-138:    N4-[3-((Ethylamino)sulfonylamino)methylphenyl]-5-fluoro-N2-[4-(4-methyl-1-piperazinyl)phenyl]-2,4-pyrimidinediamine;-   II-139:    N4-[3-((Ethylamino)sulfonylamino)methylphenyl]-5-fluoro-N2-[3-methyl-4-(4-methyl-1-piperazinyl)phenyl]-2,4-pyrimidinediamine;-   II-140:    5-Chloro-N4-[4-[N-(Cyclopropylsulfonyl)-N′-((3-ethoxycarbonyl)propion-1-yl)amino]methylphenyl]-N2-(3,5-dimethyl-4-methoxyphenyl)-2,4-pyrimidinediamine;-   II-141:    5-Chloro-N4-[4-[N-cyclopropylsulfonyl)-N′-(3-(4-morpholine)propion-1-yl)amino]methylphenyl]-N2-(3,5-dimethyl-4-methoxyphenyl)-2,4-pyrimidinediamine;-   II-142:    5-Chloro-N2-(3,5-dimethyl-4-methoxyphenyl)-N4-[2-methyl-4-(ethylaminosulfonylamino)methylphenyl]-2,4-pyrimidinediamine;-   II-143:    5-Chloro-N2-(3,5-dimethyl-4-ethoxyphenyl)-N4-[2-methyl-4-(ethylaminosulfonylamino)methylphenyl]-2,4-pyrimidinediamine;-   II-144:    5-Chloro-N4-[2-methyl-4-(ethylaminosulfonylamino)methylphenyl]-N2-[4-(4-methyl-1-piperazinyl)phenyl]-2,4-pyrimidinediamine;-   II-145:    5-Chloro-N4-[2-methyl-4-(ethylaminosulfonylamino)methylphenyl]-N2-[3-methyl-4-(4-methyl-1-piperazinyl)phenyl]-2,4-pyrimidinediamine;-   II-146:    N4-[4-(Aminosulfonylamino)methylphenyl]-5-chloro-N2-(3,5-dimethyl-4-methoxyphenyl)-2,4-pyrimidinediamine;-   II-147:    N4-[4-(Aminosulfonylamino)methylphenyl]-5-chloro-N2-(3,5-Dimethyl-4-ethoxyphenyl)-2,4-pyrimidinediamine;-   II-148:    N4-[4-(Aminosulfonylamino)methylphenyl]-5-chloro-N2-[4-(4-methyl-1-piperazinyl)phenyl]-2,4-pyrimidinediamine;-   II-149:    N4-[4-(Aminosulfonylamino)methylphenyl]-5-chloro-N2-[3-methyl-4-(4-methyl-1-piperazinyl)phenyl]-2,4-pyrimidinediamine;-   II-150:    5-Chloro-N2-(3,5-dimethyl-4-methoxyphenyl)-N4-[2-methyl-4-(N-cyclopropylsulfonylamino)methylphenyl]-2,4-pyrimidinediamine;-   II-151:    5-Chloro-N2-(3,5-dimethyl-4-ethoxyphenyl)-N4-[2-methyl-4-(N-cyclopropylsulfonylamino)methylphenyl]-2,4-pyrimidinediamine;-   II-152:    5-Chloro-N4-[2-methyl-4-(N-cyclopropylsulfonylamino)methylphenyl]-N2-[4-(4-methyl-1-piperazinyl)phenyl]-2,4-pyrimidinediamine;-   II-153:    5-Chloro-N4-[2-methyl-4-(N-cyclopropylsulfonylamino)methylphenyl]-N2-[3-methyl-4-(4-methyl-1-piperazinyl)phenyl]-2,4-pyrimidinediamine;-   II-154:    5-Chloro-N4-[4-((N-cyclopropylamino)sulfonylamino)methylphenyl]-N2-(3,5-dimethyl-4-methoxyphenyl)-2,4-pyrimidinediamine;-   II-155:    5-Chloro-N4-[4-((N-cyclopropylamino)sulfonylamino)methylphenyl]-N2-(3,5-dimethyl-4-ethoxyphenyl)-2,4-pyrimidinediamine;-   II-156:    5-Chloro-N4-[4-((N-cyclopropylamino)sulfonylamino)methylphenyl]-N2-(3,5-dimethyl-4-(1-methyl)ethoxyphenyl)-2,4-pyrimidinediamine;-   II-157:    5-Chloro-N4-[4-((N-cyclopropylamino)sulfonylamino)methylphenyl]-N2-(3,5-dimethyl-4-propoxyphenyl)-2,4-pyrimidinediamine;-   II-158:    5-Chloro-N4-[4-((N-cyclopropylamino)sulfonylamino)methylphenyl]-N2-(3,4-dimethoxy-5-methylphenyl)-2,4-pyrimidinediamine;-   II-159:    N4-[4-(N-Cyclopropylsulfonylamino)methylphenyl]-N2-[3,4-dimethyl-4-(2-(4-morpholinyl)ethoxy)phenyl]-5-methyl-2,4-pyrimidinediamine;-   II-160:    5-Chloro-N4-[4-(N-cyclopropylsulfonylamino)methylphenyl]-N2-[3,4-dimethyl-4-(2-(4-morpholinyl)ethoxy)phenyl]-2,4-pyrimidinediamine;-   II-161:    N2-[3,4-Dimethyl-4-(2-(4-morpholinyl)ethoxy)phenyl]-5-methyl-N4-[2-methyl-4-(N-cyclopropylsulfonylamino)methylphenyl]-2,4-pyrimidinediamine;-   II-162:    N4-[4-((N-Cyclopropylamino)sulfonylamino)methylphenyl]-N2-(3,5-dimethyl-4-methoxyphenyl)-5-methyl-2,4-pyrimidinediamine;-   II-163:    N4-[4-((N-Cyclopropylamino)sulfonylamino)methylphenyl]-N2-(3,5-dimethyl-4-ethoxyphenyl)-5-methyl-2,4-pyrimidinediamine;-   II-164:    N4-[4-((N-Cyclopropylamino)sulfonylamino)methylphenyl]-N2-[3,5-dimethyl-4-(1-methyl)ethoxyphenyl]-5-methyl-2,4-pyrimidinediamine;-   II-165:    N4-[4-((N-Cyclopropylamino)sulfonylamino)methylphenyl]-N2-(3,5-dimethyl-4-propoxyphenyl)-5-Methyl-2,4-pyrimidinediamine;-   II-166:    N4-[4-((N-Cyclopropylamino)sulfonylamino)methylphenyl]-N2-(3,4-dimethoxy-5-methylphenyl)-5-methyl-2,4-pyrimidinediamine;-   II-167:    5-Chloro-N4-[4-((N-cyclopropylamino)sulfonylamino)methylphenyl]-N2-[4-(4-methyl-1-piperazinyl)phenyl]-2,4-pyrimidinediamine;-   II-168:    5-Chloro-N4-[4-((N-cyclopropylamino)sulfonylamino)methylphenyl]-N2-[3-methyl-4-(4-methyl-1-piperazinyl)phenyl]-2,4-pyrimidinediamine;-   II-169:    5-Chloro-N4-[4-((N-cyclopropylamino)sulfonylamino)methylphenyl]-N2-[6-(4-methyl-1-piperazinyl)-3-pyridinyl]-2,4-pyrimidinediamine;-   II-170:    5-Chloro-N2-[3,4-dimethyl-4-(2-(4-morpholinyl)ethoxy)phenyl]-N4-[4-((N-cyclopropylamino)sulfonylamino)methylphenyl]-2,4-pyrimidinediamine;-   II-171:    N4-[4-((N-Cyclopropylamino)sulfonylamino)methylphenyl]-5-methyl-N2-[4-(4-methyl-1-piperazinyl)phenyl]-2,4-pyrimidinediamine;-   II-172:    N4-[4-((N-Cyclopropylamino)sulfonylamino)methylphenyl]-5-methyl-N2-[3-methyl-4-(4-methyl-1-piperazinyl)phenyl]-2,4-pyrimidinediamine;-   II-173:    N4-[4-((N-Cyclopropylamino)sulfonylamino)methylphenyl]-5-methyl-N2-[6-(4-methyl-1-piperazinyl)-3-pyridinyl]-2,4-pyrimidinediamine;-   II-174:    N2-[3,4-Dimethyl-4-(2-(4-morpholinyl)ethoxy)phenyl]-N4-[4-((N-cyclopropylamino)sulfonylamino)methylphenyl]-5-methyl-2,4-pyrimidinediamine;-   II-175:    5-Chloro-N2-(3,5-dimethyl-4-methoxyphenyl)-N4-[2-methyl-4-((N-cyclopropylamino)sulfonylamino)methylphenyl]-2,4-pyrimidinediamine;-   II-176:    5-Chloro-N2-(3,5-dimethyl-4-ethoxyphenyl)-N4-[2-methyl-4-((N-cyclopropylamino)sulfonylamino)methylphenyl]-2,4-pyrimidinediamine;-   II-177:    5-Chloro-N2-(3,5-dimethyl-4-(1-methylethoxy)phenyl)-N4-[2-methyl-4-((N-cyclopropylamino)sulfonylamino)methylphenyl]-2,4-pyrimidinediamine;-   II-178:    5-Chloro-N2-(3,5-dimethyl-4-propoxyphenyl)-N4-[2-methyl-4-((N-cyclopropylamino)sulfonylamino)methylphenyl]-2,4-pyrimidinediamine;-   II-179:    5-Chloro-N2-(3,4-dimethoxy-5-methylphenyl)-N4-[2-methyl-4-((N-cyclopropylamino)sulfonylamino)methylphenyl]-2,4-pyrimidinediamine;-   II-180:    5-Chloro-N4-[2-methyl-4-((N-cyclopropylamino)sulfonylamino)methylphenyl]-N2-[4-(4-methyl-1-piperazinyl)phenyl]-2,4-pyrimidinediamine;-   II-181:    5-Chloro-N4-[2-methyl-4-((N-cyclopropylamino)sulfonylamino)methylphenyl]-N2-[3-methyl-4-(4-methyl-1-piperazinyl)phenyl]-2,4-pyrimidinediamine;-   II-182:    5-Chloro-N4-[2-methyl-4-((N-cyclopropylamino)sulfonylamino)methylphenyl]-N2-[6-(4-methyl-1-piperazinyl)-3-pyridinyl]-2,4-pyrimidinediamine;-   II-183:    5-Chloro-N2-[3,4-dimethyl-4-(2-(4-morpholinyl)ethoxy)phenyl]-N4-[2-methyl-4-((N-cyclopropylamino)sulfonylamino)methylphenyl]-2,4-pyrimidinediamine;-   II-184:    N4-[4-(N-Cyclopropylsulfonylamino)methylphenyl]-5-methyl-N2-[3-methyl-4-[(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]phenyl]-2,4-pyrimidinediamine;-   II-185:    5-Chloro-N4-[4-(N-Cyclopropylsulfonylamino)methylphenyl]-N2-[3-methyl-4-[(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]phenyl]-2,4-pyrimidinediamine;-   II-186:    5-Chloro-N4-[4-(N-cyclopropylsulfonylaminomethyl)phenyl]-N2-[3,4,5-trimethoxyphenyl]-2,4-pyrimidinediamine;-   II-187:    5-Chloro-N4-[4-(N-cyclopropylsulfonylaminomethyl)phenyl]-N2-[4-(N-methylpiperidin-4-yl)phenyl]-2,4-pyrimidinediamine;-   II-188:    5-Chloro-N4-[4-(N-cyclopropylsulfonylamino)methylphenyl]-N2-[4-(N-methylpiperizin-4-yl)phenyl]-2,4-pyrimidinediamine;-   II-189:    5-Chloro-N4-[3-(N-cyclopropylsulfonylamino)methylphenyl]-N2-[3,4,5-trimethoxyphenyl]-2,4-pyrimidinediamine;-   II-190:    5-Chloro-N4-[3-(N-cyclopropylsulfonylaminomethyl)phenyl]-N2-[4-(N-methylpiperidin-4-yl)phenyl]-2,4-pyrimidinediamine;-   II-191:    5-Chloro-N4-[3-(N-cyclopropylsulfonylamino)methylphenyl]-N2-[4-(N-methylpiperizin-4-yl)phenyl]-2,4-pyrimidinediamine;-   II-192:    5-Chloro-N4-[3-(N-cyclopropylsulfonylamino)methylphenyl]-N2-[3,5-dimethyl-4-methoxyphenyl]-2,4-pyrimidinediamine;-   II-193:    5-Chloro-N4-[4-(N-cyclopropylsulfonylamino)methylphenyl]-N2-[4-(3-pyridinyl)phenyl]-2,4-pyrimidinediamine;-   II-194:    5-Chloro-N4-[3-(N-cyclopropylsulfonylamino)methylphenyl]-N2-[4-(3-pyridinyl)phenyl]-2,4-pyrimidinediamine;-   II-195:    5-Fluoro-N4-[4-(N-cyclopropylsulfonylamino)methylphenyl]-N2-[3,4-dimethoxy-5-methylphenyl]-2,4-pyrimidinediamine-   II-196:    5-Fluoro-N4-[4-(N-cyclopropylsulfonylamino)methylphenyl]-N2-[3,4-dimethoxy-5-chlorophenyl]-2,4-pyrimidinediamine;-   II-197:    5-Methyl-N4-[4-(N-cyclopropylsulfonylamino)methylphenyl]-N2-[3,4-dimethoxy-5-methylphenyl]-2,4-pyrimidinediamine;-   II-198:    5-Methyl-N4-[4-(N-cyclopropylsulfonylamino)methylphenyl]-N2-[3,4-dimethoxy-5-chlorophenyl]-2,4-pyrimidinediamine;-   II-199:    5-Chloro-N4-[4-(N-cyclopropylsulfonylamino)methylphenyl]-N2-[3,4-dimethoxy-5-methylphenyl]-2,4-pyrimidinediamine;-   II-200:    5-Chloro-N4-[4-(N-cyclopropylsulfonylamino)methylphenyl]-N2-[3,4-dimethoxy-5-chlorophenyl]-2,4-pyrimidinediamine;-   II-201:    5-Methyl-N4-[4-(N-cyclopropylsulfonylamino)methylphenyl]-N2-[3,5-dimethyl-4-methoxyphenyl]-2,4-pyrimidinediamine;-   II-202:    5-Methyl-N4-[4-(N-cyclopropylsulfonylamino)methylphenyl]-N2-[3-methyl-4-(N-methylpiperizin-4-yl)phenyl]-2,4-pyrimidinediamine;-   II-203:    5-Chloro-N4-[4-(N-cyclopropylsulfonylamino)methylphenyl]-N2-[3-methyl-4-(N-methylpiperizin-4-yl)phenyl]-2,4-pyrimidinediamine;-   II-204:    5-Methyl-N4-[4-(N-cyclopropylsulfonylamino)methylphenyl]-N2-[4-(N-ethylpiperizin-4-yl)phenyl]-2,4-pyrimidinediamine;-   II-205:    5-Chloro-N4-[4-(N-cyclopropylsulfonylamino)methylphenyl]-N2-[4-(N-ethylpiperizin-4-yl)phenyl]-2,4-pyrimidinediamine;-   II-206:    5-Methyl-N4-[4-(N-cyclopropylsulfonylamino)methylphenyl]-N2-[4-[N-(methansulfonyl)piperizin-4-ylphenyl]-2,4-pyrimidinediamine;-   II-207:    5-Chloro-N4-[4-(N-cyclopropylsulfonylamino)methylphenyl]-N2-[4-[N-(methansulfonyl)piperizin-4-ylphenyl]-2,4-pyrimidinediamine;-   II-208:    5-chloro-N2-(3-Methyl-4,5-dimethoxyphenyl)-N4-[(4-(ethylamino)sulfonylamino)methylphenyl]-2,4-pyrimidinediamine;-   II-209:    5-Methyl-N4-[4-(N-cyclopropylsulfonylamino)methylphenyl]-N2-[3,4-dimethoxy-5-ethoxyphenyl]-2,4-pyrimidinediamine;-   II-210:    5-Chloro-N4-[4-(N-cyclopropylsulfonylamino)methylphenyl]-N2-[3,4-dimethoxy-5-ethoxyphenyl]-2,4-pyrimidinediamine;-   II-211:    5-Chloro-N4-[4-(N-cyclopropylsulfonylamino)methylphenyl]-N2-[3,5-dimethyl-4-ethoxyphenyl]-2,4-pyrimidinediamine;-   II-212:    5-Methyl-N4-[4-(N-cyclopropylsulfonylamino)methylphenyl]-N2-[2,4-dimethyl-5-chlorophenyl]-2,4-pyrimidinediamine;-   II-213:    5-Chloro-N4-[4-(N-cyclopropylsulfonylamino)methylphenyl]-N2-[2,4-dimethyl-5-chlorophenyl]-2,4-pyrimidinediamine;-   II-214:    5-Methyl-N4-[4-(N-cyclopropylsulfonylamino)methylphenyl]-N2-[3,5-dimethyl-4-ethoxyphenyl]-2,4-pyrimidinediamine;-   II-215:    5-Methyl-N4-[4-(N-cyclopropylsulfonylamino)methylphenyl]-N2-[4-(N-methylpiperizin-4-yl)pyridine-3-yl]-2,4-pyrimidinediamine;-   II-216:    5-Chloro-N4-[4-(N-cyclopropylsulfonylamino)methylphenyl]-N2-[4-(N-methylpiperizin-4-yl)pyridine-3-yl]-2,4-pyrimidinediamine;-   II-217:    5-Chloro-N4-[4-(N-cyclopropyl-N-acetylsulfonylamino)methylphenyl]-N2-[3,4-dimethyl-5-methoxyphenyl]-2,4-pyrimidinediamine;-   II-218:    5-Chloro-N4-[4-(N-cyclopropyl-N-propionylsulfonylamino)methylphenyl]-N2-[3,5-dimethyl-4-methoxyphenyl]-2,4-pyrimidinediamine;-   II-219:    5-Methyl-N4-[4-(N-cyclopropylsulfonylamino)methylphenyl]-N2-[3,5-dimethyl-4-(2-propoxy)phenyl]-2,4-pyrimidinediamine;-   II-220:    5-Chloro-N4-[4-(N-cyclopropylsulfonylamino)methylphenyl]-N2-[3,5-dimethyl-4-(2-propoxy)phenyl]-2,4-pyrimidinediamine;-   II-221:    5-Chloro-N4-[4-(N-cyclopropylsulfonylamino)methylphenyl]-N2-[3,5-dimethyl-4-(1-propoxy)phenyl]-2,4-pyrimidinediamine;-   II-222:    5-Methyl-N4-[4-(N-cyclopropylsulfonylamino)methylphenyl]-N2-[4-(1-morpholinomethyl)phenyl]-2,4-pyrimidinediamine;-   II-223:    5-Chloro-N4-[4-(N-cyclopropylsulfonylamino)methylphenyl]-N2-[4-(1-morpholinomethyl)phenyl]-2,4-pyrimidinediamine;-   II-224:    5-Methyl-N4-[4-(N-cyclopropylsulfonylamino)methylphenyl]-N2-[5-methyl-4-(N-methylpiperizin-4-yl)pyridin-3-yl]-2,4-pyrimidinediamine;-   II-225:    5-Chloro-N4-[4-(N-cyclopropylsulfonylamino)methylphenyl]-N2-[5-methyl-4-(N-methylpiperizin-4-yl)pyridin-3-yl]-2,4-pyrimidinediamine;-   III-1:    N4-[4-(Cyclopropylsulfonylaminomethyl)phenyl]-5-fluoro-N2-[1-(2-(N-morpholino)ethyl)indol-6-yl]-2,4-pyrimidinediamine;-   III-2:    N4-[4-(Cyclopropylsulfonylaminomethyl)phenyl]-5-fluoro-N2-[1-(2-(N-morpholino)ethylaminocarbonyl)indol-6-yl]-2,4-pyrimidinediamine;-   III-3:    N4-(4-cyclopropylsulfonylaminomethyl)phenyl-5-methyl-N2-(2-methylbenzoimidazol-5-yl)-2,4-pyrimidinediamine;-   III-4:    N4-(3-cyclopropylsulfonylaminomethyl)phenyl-5-methyl-N2-(2-methylbenzoimidazol-5-yl)-2,4-pyrimidinediamine;-   III-5:    N4-(4-cyclopropylsulfonylaminomethyl)phenyl-5-fluoro-N2-(2-methylbenzoimidazol-5-yl)-2,4-pyrimidinediamine;-   III-6:    5-chloro-N4-(4-cyclopropylsulfonylaminomethyl)phenyl-N2-(2-methylbenzoimidazol-5-yl)-2,4-pyrimidinediamine;-   III-7:    5-Chloro-N4-[3-(N-cyclopropylsulfonylaminomethyl)phenyl]-N2-[2-methylbenzamidazol-5-yl]-2,4-pyrimidinediamine;-   IV-1:    N2-(benzoimidazol-5-yl)-N4-(4-cyclopropylsulfonylaminomethyl)phenyl-5-methyl-2,4-pyrimidinediamine;-   IV-2:    N4-(4-cyclopropylsulfonylaminomethyl)phenyl-5-methyl-N2-(2-trifluoromethylbenzoimidazol-5-yl)-2,4-pyrimidinediamine;-   IV-3:    N4-(4-cyclopropylsulfonylaminomethyl)phenyl-5-methyl-N2-[2-(pyridin-3-yl)benzoimidazol-5-yl]-2,4-pyrimidinediamine;-   IV-4:    N2-(2-tert-butylbenzoimidazol-5-yl)-N4-(4-cyclopropylsulfonylaminomethyl)phenyl-5-methyl-2,4-pyrimidinediamine;-   IV-5:    N4-(4-cyclopropylsulfonylaminomethyl)phenyl-5-methyl-N2-[2-(thien-2-yl)benzoimidazol-5-yl]-2,4-pyrimidinediamine;-   IV-6:    N4-(4-cyclopropylsulfonylaminomethyl)phenyl-5-methyl-N2-[2-(morpholin-4-yl)methylbenzoimidazol-5-yl]-2,4-pyrimidinediamine;-   IV-7:    N4-(4-cyclopropylsulfonylaminomethyl)phenyl-N2-(1,2-dimethylbenzoimidazol-5-yl)-5-methyl-2,4-pyrimidinediamine;-   IV-8:    N4-(4-cyclopropylsulfonylaminomethyl)phenyl-N2-[1-(2-hydroxyethyl)benzoimidazol-5-yl]-5-methyl-2,4-pyrimidinediamine;-   IV-9:    N4-(3-cyclopropylsulfonylaminomethyl)phenyl-N2-[1-(2-hydroxyethyl)benzoimidazol-5-yl]-5-methyl-2,4-pyrimidinediamine;-   IV-10:    N4-(3-cyclopropylsulfonylaminomethyl)phenyl-N2-(1,2-dimethylbenzoimidazol-5-yl)-5-methyl-2,4-pyrimidinediamine;-   IV-11:    N4-(3-cyclopropylsulfonylaminomethyl)phenyl-5-methyl-N2-[2-(thien-2-yl)benzoimidazol-5-yl]-2,4-pyrimidinediamine;-   IV-12:    N4-(3-cyclopropylsulfonylaminomethyl)phenyl-5-methyl-N2-[2-(pyridin-3-yl)benzoimidazol-5-yl]-2,4-pyrimidinediamine;-   IV-13:    N2-(benzoimidazol-5-yl)-N4-(3-cyclopropylsulfonylaminomethyl)phenyl-5-methyl-2,4-pyrimidinediamine;-   IV-14:    N4-(3-cyclopropylsulfonylaminomethyl)phenyl-5-methyl-N2-(2-trifluoromethylbenzoimidazol-5-yl)-2,4-pyrimidinediamine;-   IV-15:    N2-(2-tert-butylbenzoimidazol-5-yl)-N4-(3-cyclopropylsulfonylaminomethyl)phenyl-5-methyl-2,4-pyrimidinediamine;-   IV-16:    N4-(3-cyclopropylsulfonylaminomethyl)phenyl-5-methyl-N2-[2-(morpholin-4-yl)methylbenzoimidazol-5-yl]-2,4-pyrimidinediamine;-   V-1:    (+/−)-5-Methyl-N4-[1-(methylsulfonylamino)indan-6-yl]-N2-(3,4,5-trimethoxypheyl)-2,4-pyrimidinediamine;-   V-2:    (+/−)-5-Methyl-N2-[4-(1-methyl-4-piperidinyl)pheny]-N4-[1-(methylsulfonyl)aminoindan-6-yl]-2,4-pyrimidinediamine;-   V-3:    (+/−)-N4-[1-(Cyclopropylsulfonylamino)indan-6-yl]-5-Methyl-N2-(3,4,5-trimethoxyphenyl))-2,4-pyrimidinediamine;-   V-4:    (+/−)-N4-[1-(Cyclopropylsulfonylamino)indan-6-yl]-5-methyl-N2-[4-(4-methyl-1-piperazinyl)phenyl]-2,4-pyrimidinediamine;-   V-5:    (+/−)-N4-[1-(Cyclopropylsulfonylamino)indan-6-yl]-5-methyl-N2-[4-(1-methyl-4-piperidinyl)pheny]-2,4-pyrimidinediamine;-   V-6:    (+/−)-N4-[1-(Cyclopropylsulfonylamino)indan-6-yl]-N2-[4-(4,5-dihydro-1H-imidazol-2-yl)phenyl]-5-methyl-2,4-pyrimidinediamine;-   V-7:    (+/−)-N4-[1-(Cyclopropylsulfonylamino)indan-6-yl]-N2-(3,5-dimethyl-4-methoxyphenyl)-5-methyl-2,4-pyrimidinediamine;-   V-8:    (+/−)-N4-[1-(Cyclopropylsulfonylamino)indan-6-yl]-N2-(3,5-dichloro-4-methoxyphenyl)-5-methyl-2,4-pyrimidinediamine;-   V-9:    (1R)-5-Methyl-N4-[(1-(methylsulfonylamino)indan-6-yl]-N2-(3,4,5-trimethoxyphenyl)-2,4-pyrimidinediamine;-   V-10:    (1R)—N2-(3,5-dimethyl-4-methoxyphenyl)-5-methyl-N4-[(1-(methylsulfonylamino)indan-6-yl]-2,4-pyrimidinediamine;-   V-11:    (1R)-5-Methyl-N2-[4-(1-methyl-4-piperidinyl)pheny]-N4-[1-(methylsulfonyl)aminoindan-6-yl]-2,4-pyrimidinediamine;-   V-12:    (1R)-5-Methyl-N4-[1-(methylsulfonyl)aminoindan-6-yl]-N2-[4-(3-pyridinyl)phenyl]-2,4-pyrimidinediamine;-   V-13:    (1R)—N2-(3,5-Dichloro-4-methoxypheyl))-5-methyl-N4-[1-(methylsulfonyl)aminoindan-6-yl]-2,4-pyrimidinediamine;-   V-14:    (1R)-5-Methyl-N2-[4-(4-methyl-1-piperazinyl)phenyl]-N4-[1-(methylsulfonyl)aminoindan-6-yl]-2,4-pyrimidinediamine;-   VI-1:    5-Chloro-N2-[4-(4-methyl-1-piperazinyl)phenyl]-N4-[1,2,3,4-tetrahydro-2-(ethylsulfonyl)-5-isoquinolinyl]-2,4-pyrimidinediamine;-   VI-2:    5-Chloro-N2-[3-methyl-4-(methyl-1-piperazinyl)phenyl]-N4-[1,2,3,4-tetrahydro-2-(ethylsulfonyl)-5-isoquinolinyl]-2,4-pyrimidinediamine;-   VI-3:    5-Chloro-N2-[6-(4-methyl-1-piperazinyl)-3-pyridinyl]-N4-[1,2,3,4-tetrahydro-2-(ethylsulfonyl)-5-isoquinolinyl]-2,4-pyrimidinediamine;-   VI-4:    5-Chloro-N2-(3,5-dimethyl-4-methoxyphenyl)N4-[1,2,3,4-tetrahydro-2-(ethylsulfonyl)-5-isoquinolinyl]-2,4-pyrimidinediamine;-   VI-5:    5-Chloro-N4-[1,2,3,4-tetrahydro-2-(ethylsulfonyl)-5-isoquinolinyl]-N2-(3,4,5-trimethoxyphenyl)-2,4-pyrimidinediamine;-   VII-1:    5-Chloro-N4-[3,4-dihydro-1,1-dioxide-2H-1,2-benzothiazin-7-yl]-N2-[3,5-dimethyl-4-methoxyphenyl]-2,4-pyrimidinediamine;-   VII-2:    5-Chloro-N4-[3,4-dihydro-1,1-dioxide-2H-1,2-benzothiazin-7-yl]-N2-[4-(N-methylpiperizin-4-yl)phenyl]-2,4-pyrimidinediamine;-   VII-3:    5-Chloro-N4-[3,4-dihydro-1,1-dioxide-2H-1,2-benzothiazin-7-yl]-N2-[4-(N-methylpiperizin-4-yl)pyridine-3-yl]-2,4-pyrimidinediamine;-   VII-4:    5-Chloro-N4-[3,4-dihydro-1,1-dioxide-2H-1,2-benzothiazin-7-yl]-N2-[5-methyl-4-(N-methylpiperizin-4-yl)pyridine-3-yl]-2,4-pyrimidinediamine;-   VII-5:    5-Chloro-N4-[3,4-dihydro-1,1-dioxide-2H-1,2-benzothiazin-7-yl]-N2-[4-(N-methylpiperizin-4-yl)phenyl]-2,4-pyrimidinediamine;-   VII-6:    5-Methyl-N4-[3,4-dihydro-1,1-dioxide-2H-1,2-benzothiazin-7-yl]-N2-[5-methyl-4-(N-methylpiperizin-4-yl)pyridine-3-yl]-2,4-pyrimidinediamine;-   VII-7:    5-Methyl-N4-[3,4-dihydro-1,1-dioxide-2H-1,2-benzothiazin-7-yl]-N2-[5-methyl-4-(N-methylpiperizin-4-yl)pyridine-3-yl]-2,4-pyrimidinediamine;-   VII-8:    5-Methyl-N4-[3,4-dihydro-1,1-dioxide-2H-1,2-benzothiazin-7-yl]-N2-[3,4,5-trimethylphenyl]-2,4-pyrimidinediamine;-   VII-9:    5-Chloro-N4-[3,4-dihydro-1,1-dioxide-2H-1,2-benzothiazin-7-yl]-N2-[3,4,5-trimethylphenyl]-2,4-pyrimidinediamine;-   VII-10:    5-Methyl-N4-[3,4-dihydro-1,1-dioxide-2H-1,2-benzothiazin-7-yl]-N2-[3,5-dimethyl-4-methoxyphenyl]-2,4-pyrimidinediamine;-   VIII-1: N4,    N6-Di(3-aminosulfonylphenyl)-5-methyl-N2-(2,2,4-trimethyl-3-oxo-2H-benz[1,4]oxazin-6-yl)-2,4,6-pyrimidinetriamine;-   VIII-2:    N2-cyclopentyl-N4-(4-cyclopropylsulfonylaminomethyl)phenyl-5-fluoro-2,4-pyrimidinediamine;-   VIII-3:    (+/−)-N2-(1,2-Dimethylbenzimidazol-5-yl)-N4-[1-(methylsulfonylamino)    indan-6-yl]-5-methyl-2,4-pyrimidinediamine;-   VIII-4:    5-Fluoro-N4-[(1-methylsulfonyl)indolin-5-yl]-N2-(2-trifluoromethylbenzimidazol-5-yl)-2,4-pyrimidinediamine;-   VIII-5:    (N4-[(1-methylsulfonyl)indolin-5-yl]-5-fluoro-N2-[3-methyl-4-(4-methylpiperazin-1-yl)phenyl]-2,4-pyrimidinediamine;-   VIII-6:    5-Fluoro-N4-[(1-methylsulfonyl)indolin-5-yl]-N2-(2-methylbenzimidazol-5-yl)-2,4-pyrimidinediamine;-   VIII-7:    N4-[(N-cyclopropylsulfonyl)-1,2,3,4-tetrahydroisoquinolin-6-yl]-N2-(3,5-dimethyl)phenyl-5-methyl-2,4-pyrimidinediamine;-   VIII-8:    5-Amino-N4-(3-aminosulfonylphenyl)-N2-(indazoline-6-yl)-2,4-pyrimidinediamine;-   VIII-9:    N4-[(N-cyclopropylsulfonyl)-1,2,3,4-tetrahydroisoquinolin-6-yl]-N2-(3,5-dimethyl-4-methoxy)phenyl-5-methyl-2,4-pyrimidinediamine;-   VIII-10:    N4-[(N-ethylsulfonyl)-1,2,3,4-tetrahydroisoquinolin-6-yl]-N2-(3,5-dimethyl-4-methoxy)phenyl-5-fluoro-2,4-pyrimidinediamine;-   VIII-11:    5-Methyl-N4-[4-(N-cyclopropylsulfonylamino)methylphenyl]-N2-[5-cyclopropylpyrazol-3-yl)-2,4-pyrimidinediamine;    and-   VIII-12:    5-Chloro-N4-[4-(N-cyclopropylsulfonylamino)methylphenyl]-N2-[5-cyclopropylpyrazol-3-yl)-2,4-pyrimidinediamine.

Those of skill in the art will appreciate that the 2,4-pyrimidinediaminecompounds described herein may include functional groups that can bemasked with progroups to create prodrugs. Such prodrugs are usually, butneed not be, pharmacologically inactive until converted into theiractive drug form. Indeed, many of the 2,4-pyrimidinediamine compoundsdescribed in this invention include promoieties that are hydrolyzable orotherwise cleavable under conditions of use. For example, ester groupscommonly undergo acid-catalyzed hydrolysis to yield the parentcarboxylic acid when exposed to the acidic conditions of the stomach orbase-catalyzed hydrolysis when exposed to the basic conditions of theintestine or blood. Thus, when administered to a subject orally,2,4-pyrimidinediamine compounds that include ester moieties can beconsidered prodrugs of their corresponding carboxylic acid, regardlessof whether the ester form is pharmacologically active.

The mechanism by which the progroup(s) metabolizes is not critical andcan be caused, for example, by hydrolysis under the acidic conditions ofthe stomach, as described above, and/or by enzymes present in thedigestive tract and/or tissues or organs of the body. Indeed, theprogroup(s) can be selected to metabolize at a particular site withinthe body. For example, many esters are cleaved under the acidicconditions found in the stomach. Prodrugs designed to cleave chemicallyin the stomach to the active 2,4-pyrimidinediamine can employ progroupsincluding such esters. Alternatively, the progroups can be designed tometabolize in the presence of enzymes such as esterases, amidases,lipolases, and phosphatases, including ATPases and kinase, etc.Progroups including linkages capable of metabolizing in vivo are wellknown and include, by way of example and not limitation, ethers,thioethers, silylethers, silylthioethers, esters, thioesters,carbonates, thiocarbonates, carbamates, thiocarbamates, ureas,thioureas, and carboxamides. In some instances, a “precursor” group thatis oxidized by oxidative enzymes such as, for example, cytochrome P450of the liver, to a metabolizable group, can be selected.

In the prodrugs, any available functional moiety can be masked with aprogroup to yield a prodrug. Functional groups within the2,4-pyrimidinediamine compounds that can be masked with progroups forinclusion in a promoiety include, but are not limited to, amines(primary and secondary), hydroxyls, sulfanyls (thiols), and carboxyls. Awide variety of progroups, as well as the resultant promoieties,suitable for masking functional groups in active 2,4-pyrimidinediaminecompounds to yield prodrugs are well-known in the art. For example, ahydroxyl functional group can be masked as a sulfonate, ester, orcarbonate promoiety, which can be hydrolyzed in vivo to provide thehydroxyl group. An amino functional group can be masked as an amide,carbamate, imine, urea, phosphenyl, phosphoryl, or sulfenyl promoiety,which can be hydrolyzed in vivo to provide the amino group. A carboxylgroup can be masked as an ester (including silyl esters and thioesters),amide, or hydrazide promoiety, which can be hydrolyzed in vivo toprovide the carboxyl group. Other specific examples of suitableprogroups and their respective promoieties will be apparent to those ofskill in the art. All of these progroups, alone or in combinations, canbe included in the prodrugs.

In some implementations of the 2,4-pyrimidinediamine compounds andmethods of using the compounds, the progroup(s) can be attached to anyavailable primary or secondary amine, including, for example, the N2nitrogen atom of the 2,4-pyrimidinediamine moiety, the N4 nitrogen atomof the 2,4-pyrimidinediamine moiety, and/or a primary or secondarynitrogen atom included in a substituent on the 2,4-pyrimidinediaminecompound.

In particular implementations of the 2,4-pyrimidinediamine compounds andmethods of using the compounds, the prodrugs described herein are2,4-pyrimidinediamine compounds that are substituted at the N4 nitrogenof the 2,4-pyrimidinediamine moiety with a substituted or unsubstitutednitrogen-containing bicyclic ring that includes at least one progroup atone or more of the following: the nitrogen atom(s) of the bicyclic ring,the N2 nitrogen of the 2,4-pyrimidinediamine moiety, and the N4 nitrogenof the 2,4-pyrimidinediamine moiety.

As noted above, the identity of the progroup is not critical, providedthat it can be metabolized under the desired conditions of use, forexample, under the acidic conditions found in the stomach and/or byenzymes found in vivo, to yield a biologically active group, e.g., the2,4-pyrimidinediamines as described herein. Thus, skilled artisans willappreciate that the progroup can comprise virtually any known orlater-discovered hydroxyl, amine or thiol protecting group. Non-limitingexamples of suitable protecting groups can be found, for example, inProtective Groups in Organic Synthesis, Greene & Wuts, 2nd Ed., JohnWiley & Sons, New York, 1991 (especially pages 10-142 (alcohols, 277-308(thiols) and 309-405 (amines) the disclosure of which is incorporatedherein by reference).

Additionally, the identity of the progroup(s) can also be selected so asto impart the prodrug with desirable characteristics. For example,lipophilic groups can be used to decrease water solubility andhydrophilic groups can be used to increase water solubility. In thisway, prodrugs specifically tailored for selected modes of administrationcan be obtained. The progroup can also be designed to impart the prodrugwith other properties, such as, for example, improved passive intestinalabsorption, improved transport-mediated intestinal absorption,protection against fast metabolism (slow-release prodrugs),tissue-selective delivery, passive enrichment in target tissues, andtargeting-specific transporters. Groups capable of imparting prodrugswith these characteristics are well-known and are described, forexample, in Ettmayer et al., 2004, J. Med. Chem. 47(10):2393-2404, thedisclosure of which is incorporated by reference. All of the variousgroups described in these references can be utilized in the prodrugsdescribed herein.

As noted above, progroup(s) may also be selected to increase the watersolubility of the prodrug as compared to the active drug. Thus, theprogroup(s) may include or can be a group(s) suitable for imparting drugmolecules with improved water solubility. Such groups are well-known andinclude, by way of example and not limitation, hydrophilic groups suchas alkyl, aryl, and arylalkyl, or cycloheteroalkyl groups substitutedwith one or more of an amine, alcohol, a carboxylic acid, a phosphorousacid, a sulfoxide, a sugar, an amino acid, a thiol, a polyol, an ether,a thioether, and a quaternary amine salt.

The suitability of any particular progroup for a desired mode ofadministration can be confirmed in biochemical assays. For example, if aprodrug is to be administered by injection into a particular tissue ororgan and the identities of the various enzyme(s) expressed in thetissue or organ are known, the particular prodrug can be tested formetabolism in biochemical assays with the isolated enzyme(s).Alternatively, the particular prodrug can be tested for metabolism tothe active 2,4-pyrimidinediamine compound with tissue and/or organextracts. Using tissue and/or organ extracts can be of particularconvenience when the identity(ies) of the enzymes expressed in thetarget tissues or organs are unknown or in instances when the isolatedenzymes are not conveniently available. Skilled artisans will be able toreadily select progroups having metabolic properties (such as kinetics)suitable for particular applications using such in vitro tests. Ofcourse, specific prodrugs could also be tested for suitable metabolismin in vitro animal models.

Numerous references teach the use and synthesis of prodrugs, including,for example, Ettmayer et al., supra and Bungaard et al., (1989) J. Med.Chem. 32(12): 2503-2507. Additionally, the preparation and use ofprodrugs of 2,4-pyrimidinediamines is specifically taught in U.S.Provisional Patent Application 60/654,620, filed Feb. 18, 2005, entitled“Pyrimidinediamine Prodrugs and their Uses,” the disclosure of which ishereby incorporated by reference in its entirety.

One of ordinary skill in the art will appreciate that many of thecompounds and prodrugs thereof, as well as the various compound speciesspecifically described and/or illustrated herein, may exhibit thephenomena of tautomerism, conformational isomerism, geometric isomerism,and/or optical isomerism. For example, the compounds and prodrugs of theinvention may include one or more chiral centers and/or double bonds andas a consequence may exist as stereoisomers, such as double-bond isomers(i.e., geometric isomers), enantiomers, diasteromers, and mixturesthereof, such as racemic mixtures. As another example, the compounds andprodrugs of the invention may exist in several tautomeric forms,including the enol form, the keto form, and mixtures thereof. As thevarious compound names, formulae and compound drawings within thespecification and claims can represent only one of the possibletautomeric, conformational isomeric, optical isomeric, or geometricisomeric forms, it should be understood that the invention encompassesany tautomeric, conformational isomeric, optical isomeric, and/orgeometric isomeric forms of the compounds or prodrugs having one or moreof the utilities described herein, as well as mixtures of these variousdifferent isomeric forms. In cases of limited rotation around the2,4-pryimidinediamine core structure, atropisomers are also possible andare also specifically included in the compounds of the invention. It isintended that the compounds encompassed herein are, with the exceptionof forms of isomerism, chemically stable and able to be isolated.

Depending upon the nature of the various substituents, the2,4-pyrimidinediamine compounds and prodrugs of the invention can be inthe form of salts. Such salts include salts suitable for pharmaceuticaluses (“pharmaceutically-acceptable salts”), salts suitable forveterinary uses, etc. Such salts can be derived from acids or bases, asis well-known in the art.

In one implementation, the salt is a pharmaceutically acceptable salt.Generally, pharmaceutically acceptable salts are those salts that retainsubstantially one or more of the desired pharmacological activities ofthe parent compound and which are suitable for administration to humans.Pharmaceutically acceptable salts include acid addition salts formedwith inorganic acids or organic acids. Inorganic acids suitable forforming pharmaceutically acceptable acid addition salts include, by wayof example and not limitation, hydrohalide acids (e.g., hydrochloricacid, hydrobromic acid, hydroiodic acid, etc.), sulfuric acid, nitricacid, phosphoric acid, and the like. Organic acids suitable for formingpharmaceutically acceptable acid addition salts include, by way ofexample and not limitation, acetic acid, trifluoroacetic acid, propionicacid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, oxalicacid, pyruvic acid, lactic acid, malonic acid, succinic acid, malicacid, maleic acid, fumaric acid, tartaric acid, citric acid, palmiticacid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid,mandelic acid, alkylsulfonic acids (e.g., methanesulfonic acid,ethanesulfonic acid, 1,2-ethane-disulfonic acid, 2-hydroxyethanesulfonicacid, etc.), arylsulfonic acids (e.g., benzenesulfonic acid,4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid,4-toluenesulfonic acid, camphorsulfonic acid, etc.),4-methylbicyclo[2.2.2]-oct-2-ene-1-carboxylic acid, glucoheptonic acid,3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid,lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoicacid, salicylic acid, stearic acid, muconic acid, and the like.

Pharmaceutically acceptable salts also include salts formed when anacidic proton present in the parent compound is either replaced by ametal ion (e.g., an alkali metal ion, an alkaline earth metal ion, or analuminum ion) or coordinates with an organic base (e.g., ethanolamine,diethanolamine, triethanolamine, N-methylglucamine, morpholine,piperidine, dimethylamine, diethylamine, triethylamine, and ammonia).

The 2,4-pyrimidinediamine compounds and prodrugs thereof, as well as thesalts thereof, may also be in the form of hydrates, solvates, andN-oxides, as is well-known in the art.

In another implementation, this invention provides a compound, orstereoisomer, tautomer, prodrug, solvate, or pharmaceutically acceptablesalt thereof, selected from Tables I-VIII.

TABLE I II

R# # R¹ (R²)_(p) (R³)_(q) X Z alk SO₂N(R⁴)R⁵ R932388 I-1 H —3,4,5-trimethoxy F CH — 3-SO₂N(H)CH₂C≡CH R932392 I-2 H 4-Me 4-OCH₂C≡CHMe CH — 3-SO₂NH₂ R932419 I-3 H 4-Me 4-OCH₂C≡CH CF₃ CH — 3-SO₂NH₂ R932442I-4 H — 3,5-dimethyl-4-methoxy F CH — 3-SO₂N(H)CH₂C≡CH R932443 I-5 H —3,5-dimethyl-4-methoxy F CH 4-CH₂— —SO₂N(H)CH₂C≡CH R935883 I-6 H —3-OCH₂CONHMe NH₂ CH — 4-SO₂NH₂ R935889 I-7 H — 3-OCH₂CONHMe NH₂ CH —3-SO₂NH₂ R935987 I-8 Me — 4-methoxy NH₂ CH — 3-SO₂NH₂ R935989 I-9 Me —4-methoxy NH₂ CH — 4-SO₂NH₂ R935995 I-10 Me — 3-methoxy NH₂ CH —3-SO₂NH₂ R935997 I-11 Me — 3-methoxy NH₂ CH — 4-SO₂NH₂ R943245 I-12 H —4-OCH₂-(pyridin-2-yl) CF₃ CH — 3-SO₂NH₂ R943367 I-13 H —4-OCH₂-(pyridin-2-yl) CF₃ CH — 4-SO₂N(H)cyclopropyl R936396 I-14 H —4-(4-methylpiperazin-1-yl) Me CH — 3-SO₂N(H)C(CH₃)₃ R949259 I-15 H —3,4,5-trimethoxy Cl CH — 3-SO₂N(H)C(CH₃)₃ R949260 I-16 H —3,5-dimethyl-4-methoxy Cl CH — 3-SO₂N(H)C(CH₃)₃ R949262 I-17 H —4-(4-methylpiperazin-1-yl) Cl CH — 3-SO₂N(H)C(CH₃)₃ R949081 I-18 H —4-(4-methylpiperazin-1-yl) Br CH — 3-SO₂N(H)C(CH₃)₃ R949083 I-19 H —4-(4-methylpiperazin-1-yl) H CH — 3-SO₂N(H)C(CH₃)₃ R949346 I-20 H —3,5-dimethyl-4-(2-morpholinoethoxy) Me CH — 3-SO₂N(H)C(CH₃)₃ R949347I-21 H — 3,5-dimethyl-4-(2-morpholinoethoxy) Cl CH — 3-SO₂N(H)C(CH₃)₃R936783 I-22 H — 3-methyl-4-((1R,4R)-5-methyl-2,5- Cl CH —3-SO₂N(H)C(CH₃)₃ diazabicyclo[2.2.1]heptan-2-yl)

TABLE II IIIa

R# # (R²)_(p) (R³)_(q) X Z alk N(R⁴) SO₂R⁵ R946272 II-1 —3,4,5-trimethoxy F CH 4-CH₂— —N(H)SO₂-cyclopropyl R946273 II-2 —3,4-difluoro F CH 4-CH₂— —N(H)SO₂-cyclopropyl R946274 II-3 —3-chloro-4-methoxy F CH 4-CH₂— —N(H)SO₂-cyclopropyl R946275 II-4 —3,5-dimethyl F CH 4-CH₂— —N(H)SO₂-cyclopropyl R946276 II-5 —3-chloro-4-cyano F CH 4-CH₂— —N(H)SO₂-cyclopropyl R946278 II-6 —3-methyl-4-(4-ethylpiperazin-1-yl) F CH 4-CH₂— —N(H)SO₂-cyclopropylR946291 II-7 — 3,5-dimethyl Me CH 4-CH₂— —N(H)SO₂-cyclopropyl R946292II-8 — 4-(4-ethylpiperazin-1-yl)-3-methyl Me CH 4-CH₂——N(H)SO₂-cyclopropyl R946293 II-9 — 3,4,5-trimethoxy Me CH 4-CH₂——N(H)SO₂-cyclopropyl R946294 II-10 — 3-chloro-4-methoxy Me CH 4-CH₂——N(H)SO₂-cyclopropyl R946306 II-11 — 3,5-dimethyl Me CH 3-CH₂——N(H)SO₂-cyclopropyl R946307 II-12 — 4-(4-ethylpiperazin-1-yl)-3-methylMe CH 3-CH₂— —N(H)SO₂-cyclopropyl R946333 II-13 — 3,4,5-trimethoxy Me CH3-CH₂— —N(H)SO₂-cyclopropyl R946334 II-14 — 3-chloro-4-methoxy Me CH3-CH₂— —N(H)SO₂-cyclopropyl R946340 II-15 — 4-CONH₂ F CH 4-CH₂——N(H)SO₂-cyclopropyl R946341 II-16 — 3-CONH₂ F CH 4-CH₂——N(H)SO₂-cyclopropyl R946342 II-17 3-Cl 4-CONH₂ Me CH 4-CH₂——N(H)SO₂-cyclopropyl R946344 II-18 3-Cl 3-CONH₂ Me CH 4-CH₂——N(H)SO₂-cyclopropyl R946345 II-19 — 4-CONH₂ Me CH 4-CH₂——N(Me)SO₂-cyclopropyl R946346 II-20 — 3-CONH₂ Me CH 4-CH₂——N(Me)SO₂-cyclopropyl R946347 II-21 — 4-CONH₂ Me CH 3-CH₂——N(Me)SO₂-cyclopropyl R946351 II-22 — 3-CONH₂ Me CH 3-CH₂——N(Me)SO₂-cyclopropyl R946352 II-23 — 4-CONH₂ Me CH 3-CH₂——N(H)SO₂-cyclopropyl R946353 II-24 — 3-CONH₂ Me CH 3-CH₂——N(H)SO₂-cyclopropyl R946354 II-25 — 4-cyano Me CH 3-CH₂——N(H)SO₂-cyclopropyl R946355 II-26 — 3-cyano Me CH 3-CH₂——N(H)SO₂-cyclopropyl R946356 II-27 — 4-cyano Me CH 4-CH₂——N(Me)SO₂-cyclopropyl R946357 II-28 — 3-cyano Me CH 4-CH₂——N(Me)SO₂-cyclopropyl R946382 II-29 — 4-cyano F CH 4-CH₂——N(H)SO₂-cyclopropyl R946383 II-30 — 3-cyano F CH 4-CH₂——N(H)SO₂-cyclopropyl R946384 II-31 — 4-CONH₂ Me CH 4-CH₂——N(H)SO₂-cyclopropyl R946385 II-32 — 3-CONH₂ Me CH 4-CH₂——N(H)SO₂-cyclopropyl R946386 II-33 — 4-cyano Me CH 4-CH₂——N(H)SO₂-cyclopropyl R946387 II-34 — 3-cyano Me CH 4-CH₂——N(H)SO₂-cyclopropyl R946391 II-35 — 3-chloro-4-methoxy Cl CH 4-CH₂——N(H)SO₂-cyclopropyl R946392 II-36 — 3,5-dimethyl Cl CH 4-CH₂——N(H)SO₂-cyclopropyl R946393 II-37 — 4-CONH₂ Cl CH 4-CH₂——N(H)SO₂-cyclopropyl R946396 II-38 3-Cl 3,5-dimethyl Me CH 4-CH₂——N(H)SO₂-cyclopropyl R946397 II-39 — 3,5-dimethyl Me CH 4-CH₂——N(Me)SO₂-cyclopropyl R946398 II-40 — 3,5-dimethyl Me CH 3-CH₂——N(Me)SO₂-cyclopropyl R946400 II-41 — 4-methoxy-3,5-dimethyl F CH 4-CH₂——N(H)SO₂-cyclopropyl R946401 II-42 — 4-methoxy-3,5-dimethyl Me CH 4-CH₂——N(H)SO₂-cyclopropyl R946402 II-43 — 4-methoxy-3,5-dimethyl Cl CH 4-CH₂——N(H)SO₂-cyclopropyl R946403 II-44 — 4-methoxy-3,5-dimethyl Me CH 3-CH₂——N(H)SO₂-cyclopropyl R913066 II-45 — 4-SO₂CF₃ Cl CH 4-CH₂CH₂——N(H)SO₂-cyclopropyl R913070 II-46 — 4-methoxy-3,5-dimethyl Cl CH4-CH₂CH₂— —N(H)SO₂-cyclopropyl R913071 II-47 — 4-ethoxy-3,5-dimethyl ClCH 4-CH₂CH₂— —N(H)SO₂-cyclopropyl R913073 II-48 —4-isopropoxy-3,5-dimethyl Cl CH 4-CH₂CH₂— —N(H)SO₂-cyclopropyl R913074II-49 — 3,5-dimethyl-4-(2-morpholinoethoxy) Cl CH 4-CH₂CH₂——N(H)SO₂-cyclopropyl R913075 II-50 — 3-methyl-4,5dimethoxy Cl CH4-CH₂CH₂— —N(H)SO₂-cyclopropyl R913076 II-51 —4-(4-methylpiperazin-1-yl) Cl CH 4-CH₂CH₂— —N(H)SO₂-cyclopropyl R913077II-52 — 3-methyl-4-(4-methylpiperazin-1-yl) Cl CH 4-CH₂CH₂——N(H)SO₂-cyclopropyl R913078 II-53 — 4-(4-methylpiperazin-1-yl) Cl N4-CH₂CH₂— —N(H)SO₂-cyclopropyl R913079 II-54 —3-CF₃-4-(n-propylpiperazin-1-yl) Cl CH 4-CH₂CH₂— —N(H)SO₂-cyclopropylR913080 II-55 — 4-(4-(methylsulfonyl)piperazin-1-yl) Cl CH 4-CH₂CH₂——N(H)SO₂-cyclopropyl R913081 II-56 — 3-fluror-4-(4-methylpiperazin-1-yl)Cl CH 4-CH₂CH₂— —N(H)SO₂-cyclopropyl R913082 II-57 —3-CF₃-4-(4-ethylpiperazin-1-yl) Cl CH 4-CH₂CH₂— —N(H)SO₂-cyclopropylR913083 II-58 — 4-phenyl Cl CH 4-CH₂CH₂— —N(H)SO₂-cyclopropyl R913084II-59 — 4-SO₂CF₃ Me CH 4-CH₂CH₂— —N(H)SO₂-cyclopropyl R913085 II-60 —4-(4-((2S)-bicyclo[2.2.1]heptan-2- Me CH 4-CH₂— —N(H)SO₂-cyclopropylyl)piperazin-1-yl) R913086 II-61 — 4-(4-((2S)-bicyclo[2.2.1]heptan-2- ClCH 4-CH₂— —N(H)SO₂-cyclopropyl yl)piperazin-1-yl) R913088 II-62 —3,5-dimethyl-4-methoxy Me CH 4-CH₂CH₂— —N(H)SO₂-cyclopropyl R913089II-63 — 3,5-dimethyl-4-ethoxy Me CH 4-CH₂CH₂— —N(H)SO₂-cyclopropylR913090 II-64 — 3,5-dimethyl-4-isopropoxy Me CH 4-CH₂CH₂——N(H)SO₂-cyclopropyl R913091 II-65 — 3,5-dimethyl-4-(2-morpholinoethoxy)Me CH 4-CH₂CH₂— —N(H)SO₂-cyclopropyl R913092 II-66 —3-methyl-4,5-dimethoxy Me CH 4-CH₂CH₂— —N(H)SO₂-cyclopropyl R913093II-67 — 4-(4-methylpiperazin-1-yl) Me CH 4-CH₂CH₂— —N(H)SO₂-cyclopropylR913094 II-68 — 3-methyl-4-(4-methylpiperazin-1-yl) Me CH 4-CH₂CH₂——N(H)SO₂-cyclopropyl R913095 II-69 — 4-(4-methylpiperazin-1-yl) Me CH4-CH₂CH₂— —N(H)SO₂-cyclopropyl R913096 II-70 —3-CF₃-4-(4-methylpiperazin-1-yl) Me CH 4-CH₂CH₂— —N(H)SO₂-cyclopropylR913097 II-71 — 3-CF₃-4-(n-propylpiperazin-1-yl) Me CH 4-CH₂CH₂——N(H)SO₂-cyclopropyl R913098 II-72 —3-CF₃-4-(4-(methlsulfonyl)piperazin- Me CH 4-CH₂CH₂——N(H)SO₂-cyclopropyl 1-yl) R913099 II-73 —3-fluoro-4-(4-methylpiperazin-1-yl) Me CH 4-CH₂CH₂— —N(H)SO₂-cyclopropylR913100 II-74 — 3-CF₃-4-(4-ethylpiperazin-1-yl) Me CH 4-CH₂CH₂——N(H)SO₂-cyclopropyl R913101 II-75 — 4-phenyl Me CH 4-CH₂CH₂——N(H)SO₂-cyclopropyl R913103 II-76 4-Me4-(4-((2S)-bicyclo[2.2.1]heptan-2- Cl CH 2-CH₂— —N(H)SO₂-cyclopropylyl)piperazin-1-yl) R913104 II-77 4-Me 4-(4-((2S)-bicyclo[2.2.1]heptan-2-Me CH 2-CH₂— —N(H)SO₂-cyclopropyl yl)piperazin-1-yl) R913107 II-78 —3-fluoro-4-(4-((2S)- Me CH 4-CH₂— —N(H)SO₂-cyclopropylbicyclo[2.2.1]heptan-2-yl)piperazin-1- yl) R913108 II-79 —3-fluoro-4-(4-((2S)- Me CH 4-CH₂— —N(H)SO₂-cyclopropylbicyclo[2.2.1]heptan-2-yl)piperazin-1- yl) R936274 II-80 —3-chloro-4-methoxy;-5-methyl Cl CH 4-CH₂— —N(H)SO₂-cyclopropyl R936308II-81 — 3,5-dimethyl-4-methoxy F CH 4-CH₂— —N(H)SO₂-cyclopropyl R936309II-82 — 3-methyl-4,5-dimethoxy Et CH 4-CH₂— —N(H)SO₂-cyclopropyl R936310II-83 — 3-chloro-4-methoxy-5-methyl Et CH 4-CH₂— —N(H)SO₂-cyclopropylR936311 II-84 — 3,5-dichloro-4-methoxy Et CH 4-CH₂— —N(H)SO₂-cyclopropylR936312 II-85 — 3,4,5-trimethoxy Et CH 4-CH₂— —N(H)SO₂-cyclopropylR936315 II-86 — 4-(4-methylpiperazin-1-yl) Et CH 4-CH₂——N(H)SO₂-cyclopropyl R936316 II-87 — 4-(4,4-difluoropiperidin-1-yl) EtCH 4-CH₂— —N(H)SO₂-cyclopropyl R936317 II-88 —4-(1-methylpiperidin-4-yl) Et CH 4-CH₂— —N(H)SO₂-cyclopropyl R936318II-89 — 4-(4-ethylpiperazin-1-yl) Et CH 4-CH₂— —N(H)SO₂-cyclopropylR936319 II-90 — 3,5-dimethyl-4-methoxy Cl CH 4-CH₂— —N(H)SO₂N(Me)₂R936320 II-91 — 3-methyl-4,5-dimethoxy Cl CH 4-CH₂— —N(H)SO₂N(Me)₂R936321 II-92 — 3-chloro-4,5-dimethoxy Cl CH 4-CH₂— —N(H)SO₂N(Me)₂R936322 II-93 — 3-chloro-4-methoxy-5-methyl Cl CH 4-CH₂— —N(H)SO₂N(Me)₂R936323 II-94 — 3,5-dichloro-4-methoxy Cl CH 4-CH₂— —N(H)SO₂N(Me)₂R936324 II-95 — 3,4,5-trimethoxy Cl CH 4-CH₂— —N(H)SO₂N(Me)₂ R936327II-96 — 4-(4-methylpiperazin-1-yl) Cl CH 4-CH₂— —N(H)SO₂N(Me)₂ R936328II-97 — 4-(4,4-difluoropiperidin-1-yl) Cl CH 4-CH₂— —N(H)SO₂N(Me)₂R936329 II-98 — 4-(1-methylpiperidin-4-yl) Cl CH 4-CH₂— —N(H)SO₂N(Me)₂R936330 II-99 — 3,5-dmethyl-4-methoxy Me CH 4-CH₂— —N(H)SO₂N(Me)₂R936331 II-100 — 3,5-dimethyl-4-methoxy H CH 4-CH₂— —N(H)SO₂-cyclopropylR936332 II-101 — 3-chloro-4-methoxy-5-methyl Me CH 4-CH₂— —N(H)SO₂N(Me)₂R936333 II-102 — 3,5-dichloro-4-methoxy Me CH 4-CH₂— —N(H)SO₂N(Me)₂R936334 II-103 — 3,4,5-trimethoxy Me CH 4-CH₂— —N(H)SO₂N(Me)₂ R936337II-104 — 4-(4-methylpiperazin-1-yl) Me CH 4-CH₂— —N(H)SO₂N(Me)₂ R936338II-105 — 4-(4,4-difluoropiperidin-1-yl) Me CH 4-CH₂— —N(H)SO₂N(Me)₂R936339 II-106 — 4-(1-methylpiperidin-4-yl) Me CH 4-CH₂— —N(H)SO₂N(Me)₂R936340 II-107 — 4-(4-ethylpiperazin-1-yl) Me CH 4-CH₂— —N(H)SO₂N(Me)₂R936341 II-108 — 3,5-dimethyl-4-methoxy Cl CH 4-CH₂— —N(H)SO₂N(H)CH₂CH₃R936342 II-109 — 3,5-dimethyl-4-methoxy Et CH 4-CH₂——N(H)SO₂-cyclopropyl R936343 II-110 — 3-chloro-4-methoxy-5-methyl Cl CH4-CH₂— —N(H)SO₂N(H)Et R936344 II-111 — 3,5-dichloro-4-methoxy Cl CH4-CH₂— —N(H)SO₂N(H)Et R936345 II-112 — 3,4,5-trimethoxy Cl CH 4-CH₂——N(H)SO₂N(H)Et R936346 II-113 — 3-chloro-4,5-dimethoxy Cl CH 4-CH₂——N(H)SO₂N(H)Et R936349 II-114 — 4-(4-methylpiperazin-1-yl) Cl CH 4-CH₂——N(H)SO₂N(H)Et R936350 II-115 — 4-(1-methylpiperidin-4-yl) Cl CH 4-CH₂——N(H)SO₂N(H)Et R936351 II-116 — 3-methyl-4,5-dimethoxy Me CH 4-CH₂——N(H)SO₂N(Me)₂ R936352 II-117 — 3-methyl-4,5-dimethoxy Me CH 4-CH₂——N(H)SO₂N(H)CH₂CH₃ R936353 II-118 — 3-chloro-4-methoxy-5-methyl Me CH4-CH₂— —N(H)SO₂N(H)Et R936354 II-119 — 3,5-dichloro-4-methoxy Me CH4-CH₂— —N(H)SO₂N(H)Et R936355 II-120 — 3,4,5-trimethoxy Me CH 4-CH₂——N(H)SO₂N(H)Et R936356 II-121 — 3-chloro-4-methoxy-5-methyl Me CH 4-CH₂——N(H)SO₂N(H)Et R936359 II-122 — 4-(4-methylpiperazin-1-yl) Me CH 4-CH₂——N(H)SO₂N(H)Et R936360 II-123 — 4-(4,4-difluoropiperidin-1-yl) Me CH4-CH₂— —N(H)SO₂N(H)Et R936361 II-124 — 4-(1-methylpiperidin-4-yl) Me CH4-CH₂— —N(H)SO₂N(H)Et R936362 II-125 — 4-(4-ethylpiperazin-1-yl) Me CH4-CH₂— —N(H)SO₂N(H)Et R936438 II-126 — 3,5-dimethyl-4-methoxy CF₃ H4-CH₂— —N(H)SO₂-cyclopropyl R936440 II-127 — 4-(4-methylpiperazin-1-yl)CF₃ CH 4-CH₂— —N(H)SO₂-cyclopropyl R936441 II-128 —3-methyl-4-(4-methylpiperazin-1-yl) CF₃ CH 4-CH₂— —N(H)SO₂-cyclopropylR936448 II-129 — 3,5-dimethyl-4-methoxy Cl CH 4-CH₂— —N(H)SO₂N(H)CH₂CH₃R936449 II-130 — 3,5-dimethyl-4-ethoxy Cl CH 4-CH₂— —N(H)SO₂N(H)CH₂CH₃R936450 II-131 — 4-(4-methylpiperazin-1-yl) Cl CH 4-CH₂——N(H)SO₂N(H)CH₂CH₃ R936451 II-132 — 3-methyl-4-(4-methylpiperazin-1-yl)Me CH 4-CH₂— —N(H)SO₂N(H)CH₂CH₃ R936454 II-133 — 3,5-dimethyl-4-methoxyMe CH 4-CH₂— —N(H)SO₂N(H)CH₂CH₃ R936455 II-134 — 3,5-dimethyl-4-ethoxyMe CH 4-CH₂— —N(H)SO₂N(H)CH₂CH₃ R936456 II-135 —4-(4-methylpiperazin-1-yl) Me CH 4-CH₂— —N(H)SO₂N(H)CH₂CH₃ R936457II-136 — 3-methyl-4-(4-methylpiperazin-1-yl) Me CH 4-CH₂——N(H)SO₂N(H)CH₂CH₃ R936460 II-137 — 3,5-dimethyl-4-methoxy F CH 4-CH₂——N(H)SO₂N(H)CH₂CH₃ R936461 II-138 — 4-(4-methylpiperazin-1-yl) F CH4-CH₂— —N(H)SO₂N(H)CH₂CH₃ R936462 II-139 —3-methyl-4-(4-methylpiperazin-1-yl) F CH 4-CH₂— —N(H)SO₂N(H)CH₂CH₃R936486 II-140 — 3,5-dimethyl-4-methoxy Cl CH 4-CH₂——N[C(O)CH₂CH₂C(O)OCH₂CH₃] SO₂-cyclopropyl R936487 II-141 —3,5-dimethyl-4-methoxy Cl CH 4-CH₂— —N[C(O)CH₂CH₂-morpholino]SO₂-cyclopropyl R936498 II-142 — 3,5-dimethyl-4-methoxy Cl CH4-CH₂— —N(H)SO₂N(H)CH₂CH₃ R936499 II-143 — 3,5-dimethyl-4-ethoxy Cl CH4-CH₂— —N(H)SO₂N(H)CH₂CH₃ R936500 II-144 — 4-(4-methylpiperazin-1-yl) ClCH 4-CH₂— —N(H)SO₂N(H)CH₂CH₃ R936501 II-145 —3-methyl-4-(4-methylpiperazin-1-yl) Cl CH 4-CH₂— —N(H)SO₂N(H)CH₂CH₃R936515 II-146 — 3,5-dimethyl-4-methoxy Cl CH 4-CH₂— N(H)SO₂NH₂ R936516II-147 — 3,5-dimethyl-4-ethoxy Cl CH 4-CH₂— N(H)SO₂NH₂ R936517 II-148 —4-(4-methylpiperazin-1-yl) Cl CH 4-CH₂— N(H)SO₂NH₂ R936518 II-149 —3-methyl-4-(4-methylpiperazin-1-yl) Cl CH 4-CH₂— N(H)SO₂NH₂ R936522II-150 2-Me 3,5-dimethyl-4-methoxy Cl CH 4-CH₂— —N(H)SO₂-cyclopropylR936523 II-151 2-Me 3,5-dimethyl-4-ethoxy Cl CH 4-CH₂——N(H)SO₂-cyclopropyl R936524 II-152 2-Me 4-(4-methylpiperazin-1-yl) ClCH 4-CH₂— —N(H)SO₂-cyclopropyl R936525 II-153 2-Me3-methyl-4-(4-methylpiperazin-1-yl) Cl CH 4-CH₂— —N(H)SO₂-cyclopropylR936529 II-154 — 3,5-dimethyl-4-methoxy Cl CH 4-CH₂——N(H)SO₂NH-cyclopropyl R936530 II-155 — 3,5-dimethyl-4-ethoxy Cl CH4-CH₂— —N(H)SO₂NH-cyclopropyl R936531 II-156 — 3,5-dimethyl-4-isopropoxyCl CH 4-CH₂— —N(H)SO₂NH-cyclopropyl R936532 II-157 —3,5-dimethyl-4-propoxy Cl CH 4-CH₂— —N(H)SO₂NH-cyclopropyl R936533II-158 — 3-methyl-4,5-dimethoxy Cl CH 4-CH₂— —N(H)SO₂NH-cyclopropylR936544 II-159 — 3,5-dimethyl-4-(2-morpholinoethoxy) Me CH 4-CH₂——N(H)SO₂-cyclopropyl R936545 II-160 —3,5-dimethyl-4-(2-morpholinoethoxy) Cl CH 4-CH₂— —N(H)SO₂-cyclopropylR936546 II-161 2-Me 3,5-dimethyl-4-(2-morpholinoethoxy) Me CH 4-CH₂——N(H)SO₂-cyclopropyl R936557 II-162 — 3,5-dimethyl-4-methoxy Me CH4-CH₂— —N(H)SO₂NH-cyclopropyl R936558 II-163 — 3,5-dimethyl-4-ethoxy MeCH 4-CH₂— —N(H)SO₂NH-cyclopropyl R936559 II-164 —3,5-dimethyl-4-isopropoxy Me CH 4-CH₂— —N(H)SO₂NH-cyclopropyl R936560II-165 — 3,5-dimethyl-4-propoxy Me CH 4-CH₂— —N(H)SO₂NH-cyclopropylR936561 II-166 — 3-methyl-4,5-dimethoxy Me CH 4-CH₂——N(H)SO₂NH-cyclopropyl R936570 II-167 — 4-(4-methylpiperazin-1-yl) Cl CH4-CH₂— —N(H)SO₂NH-cyclopropyl R936571 II-168 —3-methyl-4-(4-methylpiperazin-1-yl) Cl CH 4-CH₂— —N(H)SO₂NH-cyclopropylR936572 II-169 — 4-(4-methylpiperazin-1-yl) Cl N 4-CH₂——N(H)S)₂NH-cyclopropyl R936573 II-170 —3,5-dimetyl-4-(2-morpholinoethoxy) Cl CH 4-CH₂— —N(H)SO₂NH-cyclopropylR936574 II-171 — 4-(4-methylpiperazin-1-yl) Me CH 4-CH₂——N(H)SO₂NH-cyclopropyl R936575 II-172 —3-methyl-4-(4-methylpiperazin-1-yl) Me CH 4-CH₂— —N(H)SO₂NH-cyclopropylR936576 II-173 — 4-(4-methylpiperazin-1-yl) Me N 4-CH2——N(H)S)2NH-cyclopropyl R936577 II-174 —3,5-dimethyl-4-(2-morpholinoethoxy) Me CH 4-CH₂— —N(H)SO₂NH-cyclopropylR936581 II-175 2-Me 3,5-dimethyl-4-methoxy Cl CH 4-CH₂——N(H)SO₂NH-cyclopropyl R936582 II-176 2-Me 3,5-dimethyl-4-ethoxy Cl CH4-CH₂— —N(H)SO₂NH-cyclopropyl R936583 II-177 2-Me3,5-dimethyl-4-isopropoxy Cl CH 4-CH₂— —N(H)SO₂NH-cyclopropyl R936584II-178 2-Me 3,5-dimethyl-4-propoxy Cl CH 4-CH₂— —N(H)SO₂NH-cyclopropylR936585 II-179 2-Me 3-methyl-4,5-dimethoxy Cl CH 4-CH₂——N(H)SO₂NH-cyclopropyl R936586 II-180 2-Me 4-(4-methylpiperazin-1-yl) ClCH 4-CH₂— —N(H)SO₂NH-cyclopropyl R936587 II-181 2-Me3-methyl-4-(4-methylpiperazin-1-yl) Cl CH 4-CH₂— —N(H)SO₂NH-cyclopropylR936588 II-182 2-Me 4-(4-methylpiperazin-1-yl) Cl N 4-CH₂——N(H)S)₂NH-cyclopropyl R936589 II-183 2-Me3,5-dimethyl-4-(2-morpholinoethoxy) Cl CH 4-CH₂— —N(H)SO₂NH-cyclopropylR936784 II-184 — 3-methyl-4-((1R,4R)-5-methyl-2,5- Me CH 4-CH₂——N(H)SO₂-cyclopropyl diazabicyclo[2.2.1]heptan-2-yl) R936785 II-185 —3-methyl-4-((1R,4R)-5-methyl-2,5- Cl CH 4-CH₂— —N(H)SO₂-cyclopropyldiazabicyclo[2.2.1]heptan-2-yl) R949096 II-186 — 3,4,5-trimethoxy Cl CH4-CH₂— —N(H)SO₂-cyclopropyl R949097 II-187 — 4-(1-methylpiperidin-4-yl)Cl CH 4-CH₂— —N(H)SO₂-cyclopropyl R949098 II-188 —4-(4-methylpiperazin-1-yl) Cl CH 4-CH₂— —N(H)SO₂-cyclopropyl R949101II-189 — 3,4,5-trimethoxy Cl CH 3-CH₂— —N(H)SO₂-cyclopropyl R949104II-190 — 4-(1-methylpiperidin-4-yl) Cl CH 3-CH₂— —N(H)SO₂-cyclopropylR949105 II-191 — 4-(4-methylpiperazin-1-yl) Cl CH 3-CH₂——N(H)SO₂-cyclopropyl R949117 II-192 — 3,5-dimethyl-4-methoxy Cl CH3-CH₂— —N(H)SO₂-cyclopropyl R949147 II-193 — 4-(pyridin-3-yl) Cl CH4-CH₂— —N(H)SO₂-cyclopropyl R949148 II-194 — 4-(pyridin-3-yl) Cl CH3-CH₂— —N(H)SO₂-cyclopropyl R949178 II-195 — 3-methyl-4,5-dimethoxy F CH4-CH₂— —N(H)SO₂-cyclopropyl R949179 II-196 — 3-chloro-4,5-dimethoxy F CH4-CH₂— —N(H)SO₂-cyclopropyl R949180 II-197 — 3-methyl-4,5-dimethoxy MeCH 4-CH₂— —N(H)SO₂-cyclopropyl R949181 II-198 — 3-chloro-4,5-dimethoxyMe CH 4-CH₂— —N(H)SO₂-cyclopropyl R949182 II-199 —3-methyl-4,5-dimethoxy Cl CH 4-CH₂— —N(H)SO₂-cyclopropyl R949185 II-200— 3-chloro-4,5-dimethoxy Cl CH 4-CH₂— —N(H)SO₂-cyclopropyl R949220II-201 — 3,5-dimethyl-4-methoxy Me CH 4-CH₂— —N(H)SO₂-cyclopropylR949226 II-202 — 3-methyl-4-(4-methylpiperazin-1-yl) Me CH 4-CH₂——N(H)SO₂-cyclopropyl R949227 II-203 —3-methyl-4-(4-methylpiperazin-1-yl) Cl CH 4-CH₂— —N(H)SO₂-cyclopropylR949228 II-204 — 4-(4-ethylpiperazin-1-yl) Me CH 4-CH₂——N(H)SO₂-cyclopropyl R949229 II-205 — 4-(4-ethylpiperazin-1-yl) Cl CH4-CH₂— —N(H)SO₂-cyclopropyl R949236 II-206 —4-(4-(methylsulfonyl)piperazin-1-yl) Me CH 4-CH₂CH₂——N(H)SO₂-cyclopropyl R949237 II-207 —4-(4-(methylsulfonyl)piperazin-1-yl) Cl CH 4-CH₂CH₂——N(H)SO₂-cyclopropyl R949241 II-208 — 3-methyl-4,5-dimethoxy Cl CH4-CH₂— —N(H)SO₂N(H)CH₂CH₃ R949246 II-209 — 3,4-dimethoxy-5-ethoxy Me CH4-CH₂— —N(H)SO₂-cyclopropyl R949247 II-210 — 3,4-dimethoxy-5-ethoxy ClCH 4-CH₂— —N(H)SO₂-cyclopropyl R949250 II-211 — 3,4-dimethyl-4-ethoxy ClCH 4-CH₂— —N(H)SO₂-cyclopropyl R949253 II-212 — 2,4-dimethoxy-3-chloroMe CH 4-CH₂— —N(H)SO₂-cyclopropyl R949254 II-213 —2,4-dimethoxy-3-chloro Cl CH 4-CH₂— —N(H)SO₂-cyclopropyl R949256 II-214— 3,5-dimethyl-4-ethoxy Me CH 4-CH₂— —N(H)SO₂-cyclopropyl R949281 II-215— 4-(4-methylpiperazin-1-yl) Me N 4-CH₂— —N(H)SO₂-cyclopropyl R949282II-216 — 4-(4-methylpiperazin-1-yl) Cl N 4-CH₂— —N(H)SO₂-cyclopropylR949283 II-217 — 3,5-dimethyl-4-methoxy Cl CH 4-CH₂——H[C(O)CH₃]SO₂-cyclopropyl R949284 II-218 — 3,5-dimethyl-4-methoxy Cl CH4-CH₂— —H[C(O)Et]SO₂-cyclopropyl R949287 II-219 —3,5-dimethyl-4-isopropoxy Me CH 4-CH₂— —N(H)SO₂-cyclopropyl R949288II-220 — 3,5-dimethyl-4-isopropoxy Cl CH 4-CH₂— —N(H)SO₂-cyclopropylR949291 II-221 — 3,5-dimethyl-4-propoxy Cl CH 4-CH₂——N(H)SO₂-cyclopropyl R949295 II-222 — 4-morpholinomethyl Me CH 4-CH₂——N(H)SO₂-cyclopropyl R949296 II-223 — 4-morpholinomethyl Cl CH 4-CH₂——N(H)SO₂-cyclopropyl R949326 II-224 —3-methyl-4-(4-methylpiperazin-1-yl) Me N 4-CH₂— —N(H)SO₂-cyclopropylR949327 II-225 — 3-methyl-4-(4-methylpiperazin-1-yl) Cl N 4-CH₂——N(H)SO₂-cyclopropyl

TABLE III IV

R# # (R³)_(q) Q X alk —N(R⁴) SO₂R⁵ R932396 III-1 1-(2-morpholinoethyl) CF 4-CH₂— —N(H)SO₂-cyclopropyl R932400 III-2

C F 4-CH₂— —N(H)SO₂-cyclopropyl R946404 III-3 2-Me N Me 4-CH₂——N(H)SO₂-cyclopropyl R946405 III-4 2-Me N Me 3-CH₂— —N(H)SO₂-cyclopropylR946461 III-5 2-Me N F 4-CH₂— —N(H)SO₂-cyclopropyl R946462 III-6 2-Me NCl 4-CH₂— —N(H)SO₂-cyclopropyl R949095 III-7 2-Me N Cl 3-CH₂——N(H)SO₂-cyclopropyl

TABLE IV V

R# # (R³)_(q) Q X alk N(R⁴) SO₂R⁵ R946501 IV-1 — N Me 4-CH₂——N(H)SO₂-cyclopropyl R946502 IV-2 2-CF₃ N Me 4-CH₂— —N(H)SO₂-cyclopropylR946503 IV-3 2-(pyridin-3-yl) N Me 4-CH₂— —N(H)SO₂-cyclopropyl R946504IV-4 2-C(CH₃)₃ N Me 4-CH₂— —N(H)SO₂-cyclopropyl R946505 IV-52-(thiophen-2-yl) N Me 4-CH₂— —N(H)SO₂-cyclopropyl R946506 IV-62-(morpholinomethyl) N Me 4-CH₂— —N(H)SO₂-cyclopropyl R946507 IV-72,3-dimethyl N Me 4-CH₂— —N(H)SO₂-cyclopropyl R946537 IV-8 3-CH₂CH₂OH NMe 4-CH₂— —N(H)SO₂-cyclopropyl R946538 IV-9 3-CH₂CH₂OH N Me 3-CH₂——N(H)SO₂-cyclopropyl R946539 IV-10 2,3-dimethyl N Me 3-CH₂——N(H)SO₂-cyclopropyl R946540 IV-11 2-(thiophen-2-yl) N Me 3-CH₂——N(H)SO₂-cyclopropyl R946541 IV-12 2-(pyridin-3-yl) N Me 3-CH₂——N(H)SO₂-cyclopropyl R946542 IV-13 — N Me 3-CH₂— —N(H)SO₂-cyclopropylR946550 IV-14 2-CF₃ N Me 3-CH₂— —N(H)SO₂-cyclopropyl R946555 IV-152-C(CH₃)₃ N Me 3-CH₂— —N(H)SO₂-cyclopropyl R946556 IV-162-(morpholinomethyl) N Me 3-CH₂— —N(H)SO₂-cyclopropyl

TABLE V

R# # R⁵ X (R³)_(q) R936212 V-1 methyl Me 3,4,5-trimethoxy R936238 V-2methyl Me 4-(1-methylpiperidin-4-yl) R936248 V-3 cyclopropyl Me3,4,5-trimethoxy R936249 V-4 cyclopropyl Me 4-(4-methylpiperazin-1-yl)R936250 V-5 cyclopropyl Me 4-(1-methylpiperidin-4-yl) R936251 V-6cyclopropyl Me 3-(4,5-dihydro-1H-imidazol-2-yl) R936258 V-7 cyclopropylMe 3,5-dimethyl-4-methoxy R936259 V-8 cyclopropyl Me3,5-dichloro-4-methoxy R936262 V-9 methyl Me 3,4,5-trimethoxy R936263V-10 methyl Me 3,5-dimethyl-4-methoxy R936264 V-11 methyl Me4-(4-methylpiperidin-1-yl) R936265 V-12 methyl Me 4-pyridin-3-yl R936266V-13 methyl Me 3,5-dichloro-4-methoxy R936267 V-14 methyl Me4-(4-methylpiperazin-1-yl)

TABLE VI

R # # R⁵ X Z (R³)_(q) R936664 VI-1 Et Cl CH 4-(4-methylpiperazin-1-yl)R936665 VI-2 Et Cl CH 3-methyl-4-(4-methylpiperazin-1-yl) R936666 VI-3Et Cl N 4-(4-methylpiperazin-1-yl) R936667 VI-4 Et Cl CH3,5-dimethyl-4-methoxy R936668 VI-5 Et Cl CH 3,4,5-trimethoxy

TABLE VII

R # # X Z (R³)_(q) R949331 VII-1  Cl CH 3,5-dimethyl-4-methoxy R949332VII-2  Cl CH 4-(4-methylpiperazin-1-yl) R949333 VII-3  Cl N4-(4-methylpiperazin-1-yl) R949334 VII-4  Cl N5-methyl-4-(4-methylpiperazin-1-yl) R949335 VII-5  Me CH4-(4-methylpiperazin-1-yl) R949336 VII-6  Me N4-(4-methylpiperazin-1-yl) R949337 VII-7  Me N5-methyl-4-(4-methylpiperazin-1-yl) R949338 VII-8  Me CH 3,4,5-dimethoxyR949340 VII-9  Cl CH 3,4,5-dimethoxy R949341 VII-10 Me CH3,5-dimethyl-4-methoxy

TABLE VIII R# # Structure R936076 VIII-1

R946277 VIII-2

R936213 VIII-3

R943368 VIII-4

R943369 VIII-5

R943370 VIII-6

R946399 VIII-7

R935910 VIII-8

R946724 VIII-9

R946725 VIII-10

R949269 VIII-11

R949270 VIII-12

D. Methods of the Invention

The present invention provides 2,4-pyrimidinediamine compounds andprodrugs thereof, as described herein, for use in therapy for theconditions described herein. The present invention further provides useof the compounds of the present invention in the manufacture of amedicament for the treatment of conditions in which targeting of the JAKpathway or inhibition of JAK kinases, particularly JAK3, aretherapeutically useful. The methods include conditions where thefunction of lymphocytes, macrophages, or mast cells is involved.Conditions in which targeting of the JAK pathway or inhibition of theJAK kinases, particularly JAK3, are therapeutically useful includeleukemia, lymphoma, transplant rejection (e.g., pancreas islettransplant rejection), bone marrow transplant applications (e.g.,graft-versus-host disease)), autoimmune diseases (e.g., rheumatoidarthritis, etc.), inflammation (e.g., asthma, etc.) and other conditionsas described in greater detail herein.

As noted previously, numerous conditions can be treated using the2,4-substituted pyrimidinediamine compounds, prodrugs thereof, andmethods of treatment as described herein. As used herein, “Treating” or“treatment” of a disease in a patient refers to (1) preventing thedisease from occurring in a patient that is predisposed or does not yetdisplay symptoms of the disease; (2) inhibiting the disease or arrestingits development; or (3) ameliorating or causing regression of thedisease. As well understood in the art, “treatment” is an approach forobtaining beneficial or desired results, including clinical results. Forthe purposes of this invention, beneficial or desired results caninclude one or more, but are not limited to, alleviation or ameliorationof one or more symptoms, diminishment of extent of a condition,including a disease, stabilized (i.e., not worsening) state of acondition, including diseases, preventing spread of disease, delay orslowing of condition, including disease, progression, amelioration orpalliation of the condition, including disease, state, and remission(whether partial or total), whether detectable or undetectable.Preferred are compounds that are potent and can be administered locallyat very low doses, thus minimizing systemic adverse effects.

The compounds described herein are potent and selective inhibitors ofJAK kinases and are particularly selective for cytokine signalingpathways containing JAK3. As a consequence of this activity, thecompounds can be used in a variety of in vitro, in vivo, and ex vivocontexts to regulate or inhibit JAK kinase activity, signaling cascadesin which JAK kinases play a role, and the biological responses effectedby such signaling cascades. For example, in one implementation, thecompounds can be used to inhibit JAK kinase, either in vitro or in vivo,in virtually any cell type expressing the JAK kinase, such as inhematopoietic cells in which, for example, JAK3 is predominantlyexpressed. They may also be used to regulate signal transductioncascades in which JAK kinases, particularly JAK3, play a role. SuchJAK-dependent signal transduction cascades include, but are not limitedto, the signaling cascades of cytokine receptors that involve the commongamma chain, such as, for example, the IL-4, IL-7, IL-5, IL-9, IL-15 andIL-21, or IL-2, IL-4, IL-7, IL-9, IL-15, and IL-21 receptor signalingcascades. The compounds may also be used in vitro or in vivo toregulate, and in particular to inhibit, cellular or biological responsesaffected by such JAK-dependent signal transduction cascades. Suchcellular or biological responses include, but are not limited to,IL-4/ramos CD23 upregulation and IL-2 mediated T-cell proliferation.Importantly, the compounds can be used to inhibit JAK kinases in vivo asa therapeutic approach towards the treatment or prevention of diseasesmediated, either wholly or in part, by a JAK kinase activity (referredto herein as “JAK kinase mediated diseases”). Non-limiting examples ofJAK kinase mediated diseases that can be treated or prevented with thecompounds include, but are not limited to, the following: allergies;asthma; autoimmune diseases such as transplant rejection (e.g., kidney,heart, lung, liver, pancreas, skin; host versus graft reaction (HVGR),and graft versus host reaction (GVHR)), rheumatoid arthritis, andamyotrophic lateral sclerosis; T-cell mediated autoimmune diseases suchas multiple sclerosis, psoriasis, and Sjogren's syndrome; Type IIinflammatory diseases such as vascular inflammation (includingvasculitis, arteritis, atherosclerosis, and coronary artery disease);diseases of the central nervous system such as stroke; pulmonarydiseases such as bronchitis obliteraus and primary pulmonaryhypertension; solid, delayed Type IV hypersensitivity reactions; andhematologic malignancies such as leukemia and lymphomas.

In one implementation, this invention provides a method of inhibiting anactivity of a JAK kinase, comprising contacting the JAK kinase with anamount of a compound effective to inhibit an activity of the JAK kinase,wherein the compound is selected from the compounds of this invention.In certain implementations of the methods described herein, the methodis carried out in vivo.

In another implementation, the present invention provides a method ofinhibiting an activity of a JAK kinase comprising contacting the JAKkinase with an amount of any compound of this invention, preferably, acompound of formula I effective to inhibit an activity of the JAKkinase:

a solvate, prodrug or pharmaceutically acceptable salt thereof, whereinring A, ring B, R¹, R², R³, X, W, p and q are as defined above forformula I.

In a preferred implementation, the compound contacted with the JAKkinase is selected from the group consisting of a compound of formulaII, III, IV, and V.

In one implementation, this invention provides a method of inhibiting anactivity of a JAK kinase, comprising contacting in vitro a JAK3 kinasewith an amount of a compound effective to inhibit an activity of the JAKkinase, wherein the compound is selected from the compounds of thisinvention.

In another implementation, this invention provides a method ofinhibiting an activity of a JAK kinase, comprising contacting in vitro aJAK3 kinase with an amount of any compound of this invention,preferably, a compound of formula I effective to inhibit an activity ofthe JAK kinase:

a solvate, prodrug or pharmaceutically acceptable salt thereof, whereinring A, ring B, R¹, R², R³, X, W, p and q are as defined above forformula I.

In a preferred implementation, the compound contacted in vitro with theJAK3 kinase is selected from the group consisting of a compound offormula II, III, IV, and V.

In a specific implementation, the compounds can be used to treat and/orprevent rejection in organ and/or tissue transplant recipients (i.e.,treat and/or prevent allorgraft rejection). Allografts can be rejectedthrough either a cell-mediated or humoral immune reaction of therecipient against transplant (histocompability) antigens present on themembranes of the donor's cells. The strongest antigens are governed by acomplex of genetic loci termed human leukocyte group A (HLA) antigens.Together with the ABO blood groups antigens, they are the chieftransplantation antigens detectable in humans.

Rejection following transplantation can generally be broken into threecategories: hyperacute, occurring hours to days followingtransplantation; acute, occurring days to months followingtransplantation; and chronic, occurring months to years followingtransplantation.

Hyperacute rejection is caused mainly by the production of hostantibodies that attack the graft tissue. In a hyperacute rejectionreaction, antibodies are observed in the transplant vascular very soonafter transplantation. Shortly thereafter, vascular clotting occurs,leading to ischemia, eventual necrosis and death. The graft infarctionis unresponsive to known immunosuppressive therapies. Because HLAantigens can be identified in vitro, pre-transplant screening is used tosignificantly reduce hyperacute rejection. As a consequence of thisscreening, hyperacute rejection is relatively uncommon today.

Acute rejection is thought to be mediated by the accumulation of antigenspecific cells in the graft tissue. The T-cell-mediated immune reactionagainst these antigens (i.e., HVGR or GVHR) is the principle mechanismof acute rejection. Accumulation of these cells leads to damage of thegraft tissue. It is believed that both CD4+ helper T-cells and CD8+cytotoxic T-cells are involved in the process and that the antigen ispresented by donor and host dendritic cells. The CD4+ helper T-cellshelp recruit other effector cells, such as macrophages and eosinophils,to the graft. Accessing T-cell activation signal transduction cascades(for example, CD28, CD40L, and CD2 cascades) are also involved.

The cell-mediated acute rejection can be reversed in many cases byintensifying immunotherapy. After successful reversal, severely damagedelements of the graft heal by fibrosis and the remainder of the graftappears normal. After resolution of acute rejection, dosages ofimmunosuppressive drugs can be reduced to very low levels.

Chronic rejection, which is a particular problem in renal transplants,often progresses insidiously despite increased immunosuppressivetherapy. It is thought to be due, in large part, to cell-mediated TypeIV hypersensitivity. The pathologic profile differs from that of acuterejection. The arterial endothelium is primarily involved with extensiveproliferation that may gradually occlude the vessel lumen, leading toischemia, fibrosis, a thickened intima, and atherosclerotic changes.Chronic rejection is mainly due to a progressive obliteration of graftvasculature and resembles a slow, vasculitic process.

In Type IV hypersensitivity, CD8 cytotoxic T-cells and CD4 helper Tcells recognize either intracellular or extracellular synthesizedantigen when it is complexed, respectively, with either Class I or ClassII MHC molecules. Macrophages function as antigen-presenting cells andrelease IL-1, which promotes proliferation of helper T-cells. HelperT-cells release interferon gamma and IL-2, which together regulatedelayed hyperactivity reactions mediated by macrophage activation andimmunity mediated by T cells. In the case of organ transplant, thecytotoxic T-cells destroy the graft cells on contact.

Since JAK kinases play a critical role in the activation of T-cells, the2,4-pyrimidinediamine compounds described herein can be used to treatand/or prevent many aspects of transplant rejection, and areparticularly useful in the treatment and/or prevention of rejectionreactions that are mediated, at least in part, by T-cells, such as HVGRor GVHR. The 2,4-pyrimidinediamine compounds can also be used to treatand/or prevent chronic rejection in transplant recipients and, inparticular, in renal transplant recipients. The compound can also beadministered to a tissue or an organ prior to transplanting the tissueor organ in the transplant recipient.

In another implementation, this invention provides a method of treatinga T-cell mediated autoimmune disease, comprising administering to apatient suffering from such an autoimmune disease an amount of acompound effective to treat the autoimmune disease wherein the compoundis selected from the compounds of the invention. In certainimplementations of the methods the autoimmune disease is multiplesclerosis (MS), psoriasis, or Sjogran's syndrome.

Therapy using the 2,4-pyrimidinediamine compounds described herein canbe applied alone, or it can be applied in combination with or adjunctiveto other common immunosuppressive therapies, such as, for example, thefollowing: mercaptopurine; corticosteroids such as prednisone;methylprednisolone and prednisolone; alkylating agents such ascyclophosphamide; calcineurin inhibitors such as cyclosporine,sirolimus, and tacrolimus; inhibitors of inosine monophosphatedehydrogenase (IMPDH) such as mycophenolate, mycophenolate mofetil, andazathioprine; and agents designed to suppress cellular immunity whileleaving the recipient's humoral immunologic response intact, includingvarious antibodies (for example, antilymphocyte globulin (ALG),antithymocyte globulin (ATG), monoclonal anti-T-cell antibodies (OKT3))and irradiation. These various agents can be used in accordance withtheir standard or common dosages, as specified in the prescribinginformation accompanying commercially available forms of the drugs (seealso: the prescribing information in the 2006 Edition of The Physician'sDesk Reference), the disclosures of which are incorporated herein byreference. Azathioprine is currently available from SalixPharmaceuticals, Inc., under the brand name AZASAN; mercaptopurine iscurrently available from Gate Pharmaceuticals, Inc., under the brandname PURINETHOL; prednisone and prednisolone are currently availablefrom Roxane Laboratories, Inc.; Methyl prednisolone is currentlyavailable from Pfizer; sirolimus (rapamycin) is currently available fromWyeth-Ayerst under the brand name RAPAMUNE; tacrolimus is currentlyavailable from Fujisawa under the brand name PROGRAF; cyclosporine iscurrent available from Novartis under the brand name SANDIMMUNE and fromAbbott under the brand name GENGRAF; IMPDH inhibitors such asmycophenolate mofetil and mycophenolic acid are currently available fromRoche under the brand name CELLCEPT and from Novartis under the brandname MYFORTIC; azathioprine is currently available from Glaxo SmithKline under the brand name IMURAN; and antibodies are currentlyavailable from Ortho Biotech under the brand name ORTHOCLONE, fromNovartis under the brand name SIMULECT (basiliximab), and from Rocheunder the brand name ZENAPAX (daclizumab).

In another implementation, the 2,4-pyrimidinediamine compounds could beadministered either in combination or adjunctively with an inhibitor ofa Syk kinase. Syk kinase is a tyrosine kinase known to play a criticalrole in Fcγ receptor signaling, as well as in other signaling cascades,such as those involving B-Cell receptor signaling (Tumer et al., (2000),Immunology Today 21:148-154) and integrins beta (1), beta (2), and beta(3) in neutrophils (Mocsavi et al., (2002), Immunity 16:547-558). Forexample, Syk kinase plays a pivotal role in high affinity IgE receptorsignaling in mast cells that leads to activation and subsequent releaseof multiple chemical mediators that trigger allergic attacks. However,unlike the JAK kinases, which help regulate the pathways involved indelayed or cell-mediated Type IV hypersensitivity reactions, Syk kinasehelps regulate the pathways involved in immediate IgE-mediated, Type Ihypersensitivity reactions. Certain compounds that affect the Sykpathway may or may not also affect the JAK pathways.

Suitable Syk inhibitory compounds are described, for example, in U.S.Patent Application Publication No. 2004/0029902; WO 03/063794; Ser. No.10/631,029 filed Jul. 29, 2003; WO 2004/014382; U.S. Patent ApplicationPublication No. 2005/0234049; PCT/US2004/24716 filed Jul. 30, 2004(WO005/016893); U.S. Patent Application Publication No. 2005/0209224;PCT/US2004/24920 filed Jul. 30, 2004; Ser. No. 60/630,808 filed Nov. 24,2004; Ser. No. 60/645,424 filed Jan. 19, 2005; and Ser. No. 60/654,620,filed Feb. 18, 2005, the disclosures of which are incorporated herein byreference. The 2,4-pyrimidinediamine described herein and Syk inhibitorycompounds could be used alone or in combination with one or moreconventional transplant rejection treatments, as described above.

In a specific implementation, the 2,4-pyrimidinediamine compounds can beused to treat or prevent these diseases in patients that are eitherinitially non-responsive (resistant) to or that become non-responsive totreatment with a Syk inhibitory compound or one of the other currenttreatments for the particular disease. The 2,4-pyrimidinediaminecompounds could also be used in combination with Syk inhibitorycompounds in patients that are Syk-compound resistant or non-responsive.Suitable Syk-inhibitory compounds with which the 2,4-pyrimidinediaminecompounds can be administered are provided supra.

In another implementation, this invention provides a method of treatinga T-cell mediated autoimmune disease, comprising administering to apatient suffering from such an autoimmune disease an amount of acompound effective to treat the autoimmune disease wherein the compoundis selected from the compounds of the invention, as described herein,and the compound is administered in combination with or adjunctively toa compound that inhibits Syk kinase with an IC₅₀ in the range of atleast 10 μM.

In another implementation, this invention provides a method of treatingor preventing allograft transplant rejection in a transplant recipient,comprising administering to the transplant recipient an amount of acompound effective to treat or prevent the allograft transplantrejection wherein the compound is selected from the compounds of theinvention, as described herein. In a further implementation, thecompound is administered to a tissue or an organ prior to transplantingthe tissue or organ in the transplant recipient.

In another implementation, this invention provides a method of treatingor preventing allograft transplant rejection in a transplant recipient,in which the rejection is acute rejection, comprising administering tothe transplant recipient an amount of a compound effective to treat orprevent the rejection, wherein the compound is selected from thecompounds of the invention.

In another implementation, this invention provides a method of treatingor preventing allograft transplant rejection in a transplant recipient,in which the rejection is chronic rejection, comprising administering tothe transplant recipient an amount of a compound effective to treat orprevent the rejection, wherein the compound is selected from thecompounds of the invention.

In another implementation, this invention provides a method of treatingor preventing allograft transplant rejection in a transplant recipient,in which the rejection is mediated by HVGR or GVHR, comprisingadministering to the transplant recipient an amount of a compoundeffective to treat or prevent the rejection, wherein the compound isselected from the compounds of this invention, as described herein.

In another implementation, this invention provides a method of treatingor preventing allograft transplant rejection in a transplant recipient,in which the allograft transplant is selected from a kidney, a heart, aliver, and a lung, comprising administering to the transplant recipientan amount of a compound effective to treat or prevent the rejection,wherein the compound is selected from the compounds of this invention,as described herein.

In another implementation, this invention provides a method of treatingor preventing allograft transplant rejection in a transplant recipient,in which the allograft transplant is selected from a kidney, a heart, aliver, and a lung, comprising administering to the transplant recipientan amount of a compound effective to treat or prevent the rejectionwherein the compound is selected from the compounds of the invention, asdescribed herein, in which the compound is administered in combinationwith or adjunctively to another immunosuppressant.

In another implementation, this invention provides a method of treatingor preventing allograft transplant rejection in a transplant recipient,in which the allograft transplant is selected from a kidney, a heart, aliver, and a lung, comprising administering to the transplant recipientan amount of a compound effective to treat or prevent the rejection,wherein the compound is selected from the compounds of the invention, asdescribed herein, in which the compound is administered in combinationwith or adjunctively to another immunosuppressant, in which theimmunosuppressant is selected from cyclosporine, tacrolimus, sirolimus,an inhibitor of IMPDH, mycophenolate, mycophanolate mofetil, ananti-T-Cell antibody, and OKT3.

The 2,4-pyrimidinediamine compounds described herein are cytokinemoderators of IL-4 signaling. As a consequence, the2,4-pyrimidinediamine compounds could slow the response of Type Ihypersensitivity reactions. Thus, in a specific implementation, the2,4-pyrimidinediamine compounds could be used to treat such reactionsand, therefore, the diseases associated with, mediated by, or caused bysuch hypersensitivity reactions (for example, allergies),prophylactically. For example, an allergy sufferer could take one ormore of the JAK selective compounds described herein prior to expectedexposure to allergens to delay the onset or progress of, or eliminatealtogether, an allergic response.

When used to treat or prevent such diseases, the 2,4-pyrimidinediaminecompounds can be administered singly, as mixtures of one or more2,4-pyrimidinediamine compounds, or in mixture or combination with otheragents useful for treating such diseases and/or the symptoms associatedwith such diseases. The 2,4-pyrimidinediamine compounds may also beadministered in mixture or in combination with agents useful to treatother disorders or maladies, such as steroids, membrane stabilizers,5-lipoxygenase (5LO) inhibitors, leukotriene synthesis and receptorinhibitors, inhibitors of IgE isotype switching or IgE synthesis, IgGisotype switching or IgG synthesis, β-agonists, tryptase inhibitors,aspirin, cyclooxygenase (COX) inhibitors, methotrexate, anti-TNF drugs,retuxin, PD4 inhibitors, p38 inhibitors, PDE4 inhibitors, andantihistamines, to name a few. The 2,4-pyrimidinediamine compounds canbe administered per se in the form of prodrugs or as pharmaceuticalcompositions, comprising an active compound or prodrug.

In another implementation, this invention provides a method of treatingor preventing a Type IV hypersensitivity reaction, comprisingadministering to a subject an amount of a compound effective to treat orprevent the hypersensitivity reaction, wherein the compound is selectedfrom the compounds of this invention, as described herein.

In another implementation, this invention provides a method of treatingor preventing a Type IV hypersensitivity reaction, which is practicalprophylactically, comprising administering to a subject an amount of acompound effective to treat or prevent the hypersensitivity reaction,wherein the compound is selected from the compounds of this invention,as described herein, and is administered prior to exposure to anallergen.

In one implementation, this invention provides a method of inhibiting asignal transduction cascade in which JAK3 kinase plays a role,comprising contacting a cell expressing a receptor involved in such asignaling cascade with a compound, wherein the compound is selected fromthe compounds of this invention, as described herein.

In another implementation, this invention provides a method ofinhibiting a signal transduction cascade in which JAK3 kinase plays arole, comprising contacting a cell expressing a receptor involved insuch a signaling cascade with any compound of this invention,preferably, a compound of formula I effective to inhibit a signaltransduction cascade in which JAK3 kinase plays a role:

a solvate, prodrug or pharmaceutically acceptable salt thereof, whereinring A, ring B, R¹, R², R³, X, W, p and q are as defined above forformula I.

In a preferred implementation, the compound contacted with the cell isselected from the group consisting of a compound of formula II, III, IV,and V.

In one implementation, this invention provides a method of treating orpreventing a JAK kinase-mediated disease, comprising administering to asubject an amount of compound effective to treat or prevent the JAKkinase-mediated disease, wherein the compound is selected from thecompounds of this invention, as described herein.

In another implementation, this invention provides a method of treatingor preventing a JAK kinase-mediated disease, comprising administering toa subject an amount of any compound of this invention, preferably, acompound of formula I effective to treat or prevent the JAKkinase-mediated disease:

a solvate, prodrug or pharmaceutically acceptable salt thereof, whereinring A, ring B, R¹, R², R³, X, W, p and q are as defined above forformula I.

In a preferred implementation, the compound administered to the subjectis selected from the group consisting of a compound of formula II, III,IV, and V.

In another implementation, this invention provides a method of treatingor preventing a JAK kinase-mediated disease, in which the JAK-mediateddisease is HVGR or GVHR, comprising administering to a subject an amountof compound effective to treat or prevent the JAK kinase-mediateddisease, wherein the compound is selected from the compounds of theinvention, as described herein.

In another implementation, this invention provides a method of treatingor preventing a JAK kinase-mediated disease, in which the JAK-mediateddisease is acute allograft rejection, comprising administering to asubject an amount of compound effective to treat or prevent the JAKkinase-mediated disease, wherein the compound is selected from thecompounds of the invention, as described herein.

In another implementation, this invention provides a method of treatingor preventing a JAK kinase-mediated disease, in which the JAK-mediateddisease is chronic allograft rejection, comprising administering to asubject an amount of compound effective to treat or prevent the JAKkinase-mediated disease, wherein the compound is selected from thecompounds of the invention, as described herein.

Active compounds of the invention typically inhibit the JAK/Statpathway. The activity of a specified compound as an inhibitor of a JAKkinase can be assessed in vitro or in vivo. In some implementations, theactivity of a specified compound can be tested in a cellular assay.Suitable assays include assays that determine inhibition of either thephosphorylation activity or ATPase activity of a JAK kinase. Thus, acompound is said to inhibit an activity of a JAK kinase if it inhibitsthe phosphorylation or ATPase activity of a JAK kinase with an IC₅₀ ofabout 20 μM or less.

“Cell proliferative disorder” refers to a disorder characterized byabnormal proliferation of cells. A proliferative disorder does not implyany limitation with respect to the rate of cell growth, but merelyindicates loss of normal controls that affect growth and cell division.Thus, in some embodiments, cells of a proliferative disorder can havethe same cell division rates as normal cells but do not respond tosignals that limit such growth. Within the ambit of “cell proliferativedisorder” is neoplasm or tumor, which is an abnormal growth of tissue.Cancer refers to any of various malignant neoplasms characterized by theproliferation of cells that have the capability to invade surroundingtissue and/or metastasize to new colonization sites.

“Hematopoietic neoplasm” refers to a cell proliferative disorder arisingfrom cells of the hematopoietic lineage. Generally, hematopoiesis is thephysiological process whereby undifferentiated cells or stem cellsdevelop into various cells found in the peripheral blood. In the initialphase of development, hematopoietic stem cells, typically found in thebone marrow, undergo a series of cell divisions to form multipotentprogenitor cells that commit to two main developmental pathways: thelymphoid lineage and the myeloid lineage. The committed progenitor cellsof the myeloid lineage differentiate into three major sub-branchescomprised of the erythroid, megakaryocyte, and granulocyte/monocytedevelopmental pathways. An additional pathway leads to formation ofdendritic cells, which are involved in antigen presentation. Theerythroid lineage gives rise to red blood cells while the megakaryocyticlineage gives rise to blood platelets. Committed cells of thegranulocyte/monocyte lineage split into granulocyte or monocytedevelopmental pathways, the former pathway leading to formation ofneutrophils, eosinophils, and basophils and the latter pathway givingrise to blood monocytes and macrophages.

Committed progenitor cells of the lymphoid lineage develop into the Bcell pathway, T cell pathway, or the non-T/B cell pathway. Similar tothe myeloid lineage, an additional lymphoid pathway appears to give riseto dendritic cells involved in antigen presentation. The B cellprogenitor cell develops into a precursor B cell (pre-B), whichdifferentiates into B cells responsible for producing immunoglobulins.Progenitor cells of the T cell lineage differentiate into precursor Tcells (pre-T) that, based on the influence of certain cytokines, developinto cytotoxic or helper/suppressor T cells involved in cell mediatedimmunity. Non-T/B cell pathway leads to generation of natural killer(NK) cells. Neoplasms of hematopoietic cells can involve cells of anyphase of hematopoiesis, including hematopoietic stem cells, multipotentprogenitor cells, oligopotent committed progenitor cells, precursorcells, and mature differentiated cells. The categories of hematopoieticneoplasms can generally follow the descriptions and diagnostic criteriaemployed by those of skill in the art (see, e.g., InternationalClassification of Disease and Related Health Problems (ICD 10), WorldHealth Organization (2003)). Hematopoietic neoplasms can also becharacterized based on the molecular features, such as cell surfacemarkers and gene expression profiles, cell phenotype exhibited by theaberrant cells, and/or chromosomal aberrations (e.g., deletions,translocations, insertions, etc.) characteristic of certainhematopoietic neoplasms, such as the Philadelphia chromosome found inchronic myelogenous leukemia. Other classifications include NationalCancer Institute Working Formulation (Cancer, 1982, 49:2112-2135) andRevised European-American Lymphoma Classification (REAL).

“Lymphoid neoplasm” refers a proliferative disorder involving cells ofthe lymphoid lineage of hematopoiesis. Lymphoid neoplasms can arise fromhematopoietic stem cells as well as lymphoid committed progenitor cells,precursor cells, and terminally differentiated cells. These neoplasmscan be subdivided based on the phenotypic attributes of the aberrantcells or the differentiated state from which the abnormal cells arise.Subdivisions include, among others, B cell neoplasms, T cell neoplasms,NK cell neoplasms, and Hodgkin's lymphoma.

“Myeloid neoplasm” refers to proliferative disorder of cells of themyeloid lineage of hematopoiesis. Neoplasms can arise from hematopoieticstem cells, myeloid committed progenitor cells, precursor cells, andterminally differentiated cells. Myeloid neoplasms can be subdividedbased on the phenotypic attributes of the aberrant cells or thedifferentiated state from which the abnormal cells arise. Subdivisionsinclude, among others, myeloproliferative diseases,myelodysplastic/myeloproliferative diseases, myelodysplastic syndromes,acute myeloid leukemia, and acute biphenotypic leukemia.

Generally, cell proliferative disorders treatable with the compoundsdisclosed herein relate to any disorder characterized by aberrant cellproliferation. These include various tumors and cancers, benign ormalignant, metastatic or non-metastatic. Specific properties of cancers,such as tissue invasiveness or metastasis, can be targeted using themethods described herein. Cell proliferative disorders include a varietyof cancers, including, among others, breast cancer, ovarian cancer,renal cancer, gastrointestinal cancer, kidney cancer, bladder cancer,pancreatic cancer, lung squamous carcinoma, and adenocarcinoma.

In some embodiments, the cell proliferative disorder treated is ahematopoietic neoplasm, which is aberrant growth of cells of thehematopoietic system. Hematopoietic malignancies can have its origins inpluripotent stem cells, multipotent progenitor cells, oligopotentcommitted progenitor cells, precursor cells, and terminallydifferentiated cells involved in hematopoiesis. Some hematologicalmalignancies are believed to arise from hematopoietic stem cells, whichhave the ability for self renewal. For instance, cells capable ofdeveloping specific subtypes of acute myeloid leukemia (AML) upontransplantation display the cell surface markers of hematopoietic stemcells, implicating hematopoietic stem cells as the source of leukemiccells. Blast cells that do not have a cell marker characteristic ofhematopoietic stem cells appear to be incapable of establishing tumorsupon transplantation (Blaire et al., 1997, Blood 89:3104-3112). The stemcell origin of certain hematological malignancies also finds support inthe observation that specific chromosomal abnormalities associated withparticular types of leukemia can be found in normal cells ofhematopoietic lineage as well as leukemic blast cells. For instance, thereciprocal translocation t(9q34;22q11) associated with approximately 95%of chronic myelogenous leukemia appears to be present in cells of themyeloid, erythroid, and lymphoid lineage, suggesting that thechromosomal aberration originates in hematopoietic stem cells. Asubgroup of cells in certain types of CML displays the cell markerphenotype of hematopoietic stem cells.

Although hematopoietic neoplasms often originate from stem cells,committed progenitor cells or more terminally differentiated cells of adevelopmental lineage can also be the source of some leukemias. Forexample, forced expression of the fusion protein Bcr/Abl (associatedwith chronic myelogenous leukemia) in common myeloid progenitor orgranulocyte/macrophage progenitor cells produces a leukemic-likecondition. Moreover, some chromosomal aberrations associated withsubtypes of leukemia are not found in the cell population with a markerphenotype of hematopoietic stem cells, but are found in a cellpopulation displaying markers of a more differentiated state of thehematopoietic pathway (Turhan et al., 1995, Blood 85:2154-2161). Thus,while committed progenitor cells and other differentiated cells may haveonly a limited potential for cell division, leukemic cells may haveacquired the ability to grow unregulated, in some instances mimickingthe self-renewal characteristics of hematopoietic stem cells (Passegueet al., Proc. Natl. Acad. Sci. USA, 2003, 100:11842-9).

In some embodiments, the hematopoietic neoplasm treated is a lymphoidneoplasm, where the abnormal cells are derived from and/or display thecharacteristic phenotype of cells of the lymphoid lineage. Lymphoidneoplasms can be subdivided into B-cell neoplasms, T and NK-cellneoplasms, and Hodgkin's lymphoma. B-cell neoplasms can be furthersubdivided into precursor B-cell neoplasm and mature/peripheral B-cellneoplasm. Exemplary B-cell neoplasms are precursor B-lymphoblasticleukemia/lymphoma (precursor B-cell acute lymphoblastic leukemia) whileexemplary mature/peripheral B-cell neoplasms are B-cell chroniclymphocytic leukemia/small lymphocytic lymphoma, B-cell prolymphocyticleukemia, lymphoplasmacytic lymphoma, splenic marginal zone B-celllymphoma, hairy cell leukemia, plasma cell myeloma/plasmacytoma,extranodal marginal zone B-cell lymphoma of MALT type, nodal marginalzone B-cell lymphoma, follicular lymphoma, mantle-cell lymphoma, diffuselarge B-cell lymphoma, mediastinal large B-cell lymphoma, primaryeffusion lymphoma, and Burkitt's lymphoma/Burkitt cell leukemia. T-celland Nk-cell neoplasms are further subdivided into precursor T-cellneoplasm and mature (peripheral) T-cell neoplasms. Exemplary precursorT-cell neoplasm is precursor T-lymphoblastic lymphoma/leukemia(precursor T-cell acute lymphoblastic leukemia) while exemplary mature(peripheral) T-cell neoplasms are T-cell prolymphocytic leukemia T-cellgranular lymphocytic leukemia, aggressive NK-cell leukemia, adult T-celllymphoma/leukemia (HTLV-1), extranodal NK/T-cell lymphoma, nasal type,enteropathy-type T-cell lymphoma, hepatosplenic gamma-delta T-celllymphoma, subcutaneous panniculitis-like T-cell lymphoma, Mycosisfungoides/Sezary syndrome, Anaplastic large-cell lymphoma, T/null cell,primary cutaneous type, Peripheral T-cell lymphoma, not otherwisecharacterized, Angioimmunoblastic T-cell lymphoma, Anaplastic large-celllymphoma, T/null cell, primary systemic type. The third member oflymphoid neoplasms is Hodgkin's lymphoma, also referred to as Hodgkin'sdisease. Exemplary diagnosis of this class that can be treated with thecompounds include, among others, nodular lymphocyte-predominantHodgkin's lymphoma, and various classical forms of Hodgkin's disease,exemplary members of which are Nodular sclerosis Hodgkin's lymphoma(grades 1 and 2), Lymphocyte-rich classical Hodgkin's lymphoma, Mixedcellularity Hodgkin's lymphoma, and Lymphocyte depletion Hodgkin'slymphoma. In various embodiments, any of the lymphoid neoplasms that areassociated with aberrant JAK activity can be treated with the JAKinhibitory compounds.

In some embodiments, the hematopoietic neoplasm treated is a myeloidneoplasm. This group comprises a large class of cell proliferativedisorders involving or displaying the characteristic phenotype of thecells of the myeloid lineage. Myeloid neoplasms can be subdivided intomyeloproliferative diseases, myelodysplastic/myeloproliferativediseases, myelodysplastic syndromes, and acute myeloid leukemias.Exemplary myeloproliferative diseases are chronic myelogenous leukemia(e.g., Philadelphia chromosome positive (t(9;22)(qq34;q11)), chronicneutrophilic leukemia, chronic eosinophilic leukemia/hypereosinophilicsyndrome, chronic idiopathic myelofibrosis, polycythemia vera, andessential thrombocythemia. Exemplary myelodysplastic/myeloproliferativediseases are chronic myelomonocytic leukemia, atypical chronicmyelogenous leukemia, and juvenile myelomonocytic leukemia. Exemplarymyelodysplastic syndromes are refractory anemia, with ringedsideroblasts and without ringed sideroblasts, refractory cytopenia(myelodysplastic syndrome) with multilineage dysplasia, refractoryanemia (myelodysplastic syndrome) with excess blasts, 5q-syndrome, andmyelodysplastic syndrome. In various embodiments, any of the myeloidneoplasms that are associated with aberrant JAK activity can be treatedwith the JAK inhibitory compounds.

In some embodiments, the JAK inhibitory compounds can be used to treatAcute myeloid leukemias (AML), which represent a large class of myeloidneoplasms having its own subdivision of disorders. These subdivisionsinclude, among others, AMLs with recurrent cytogenetic translocations,AML with multilineage dysplasia, and other AML not otherwisecategorized. Exemplary AMLs with recurrent cytogenetic translocationsinclude, among others, AML with t(8;21)(q22;q22), AML1(CBF-alpha)/ETO,Acute promyelocytic leukemia (AML with t(15;17)(q22;q11-12) andvariants, PML/RAR-alpha), AML with abnormal bone marrow eosinophils(inv(16)(p13q22) or t(16;16)(p13;q11), CBFb/MYH11X), and AML with 11q23(MLL) abnormalities. Exemplary AML with multilineage dysplasia are thosethat are associated with or without prior myelodysplastic syndrome.Other acute myeloid leukemias not classified within any definable groupinclude, AML minimally differentiated, AML without maturation, AML withmaturation, Acute myelomonocytic leukemia, Acute monocytic leukemia,Acute erythroid leukemia, Acute megakaryocytic leukemia, Acutebasophilic leukemia, and Acute panmyelosis with myelofibrosis.

One means of assaying for such inhibition is detection of the effect ofthe 2,4-pyrimidinediamine compounds on the upregulation of downstreamgene products. In the Ramos/IL4 assay, B-cells are stimulated with thecytokine Interleukin-4 (IL-4) leading to the activation of the JAK/Statpathway through phosphorylation of the JAK family kinases, JAK1 andJAK3, which in turn phosphorylate and activate the transcription factorStat-6. One of the genes upregulated by activated Stat-6 is the lowaffinity IgE receptor, CD23. To study the effect of inhibitors (e.g.,the 2,4-substituted pyrimindinediamine compounds described herein) onthe JAK1 and JAK3 kinases, human Ramos B cells are stimulated with humanIL-4. 20 to 24 hours post stimulation, cells are stained forupregulation of CD23 and analyzed using flow cytometry (FACS). Areduction of the amount of CD23 present compared to control conditionsindicates the test compound actively inhibits the JAK kinase pathway. Anexemplary assay of this type is described in greater detail in Example2.

The activity of the active compounds of the invention may further becharacterized by assaying the effect of the 2,4-pyrimidinediaminecompounds described herein on the proliferative response of primaryhuman T-cells. In this assay, primary human T-cells derived fromperipheral blood and pre-activated through stimulation of the T-cellreceptor and CD28, proliferate in culture in response to the cytokineInterleukin-2 (IL-2). This proliferative response is dependent on theactivation of JAK1 and JAK3 tyrosine kinases, which phosphorylate andactivate the transcription factor Stat-5. The primary human T-cells areincubated with the 2,4-pyrimidinediamine compounds in the presence ofIL-2 for 72 hours, and at the assay endpoint intracellular ATPconcentrations are measured to assess cell viability. A reduction incell proliferation compared to control conditions is indicative ofinhibition of the JAK kinase pathway.

The activity of the compounds of the invention may additionally becharacterized by assaying the effect of the 2,4-pyrimidinediaminecompounds described herein on A549 lung epithelial cells and U937 cells.A549 lung epithelial cells and U937 cells up-regulate ICAM-1 (CD54)surface expression in response to a variety of different stimuli.Therefore, using ICAM-1 expression as readout, test compound effects ondifferent signaling pathways can be assessed in the same cell type.Stimulation with IL-1β through the IL-1β receptor activates theTRAF6/NFκB pathway resulting in up-regulation of ICAM-1. IFNγ inducesICAM-1 up-regulation through activation of the JAK1/JAK2 pathway. Theup-regulation of ICAM-1 can be quantified by flow cytometry across acompound dose curve and EC₅₀ values are calculated.

Active compounds as described herein generally inhibit the JAK kinasepathway with an IC₅₀ in the range of about 1 mM or less, as measured inthe assays described herein. Of course, skilled artisans will appreciatethat compounds which exhibit lower IC₅₀s, (on the order, for example, of100 μM, 75 μM, 50 μM, 40 μM, 30 μM, 20 μM, 15 μM, 10 μM, 5 μM, 1 μM, 500nM, 100 nM, 10 nM, 1 nM, or even lower) can be particularly useful intherapeutic applications. In instances where activity specific to aparticular cell type is desired, the compound can be assayed foractivity with the desired cell type and counter-screened for a lack ofactivity against other cell types. The desired degree of “inactivity” insuch counter screens, or the desired ratio of activity vs. inactivity,may vary for different situations and can be selected by the user.

The 2,4-pyrimidinediamine active compounds also typically inhibit IL-4stimulated expression of CD23 in B-cells with an IC₅₀ in the range ofabout 100 μM or less, preferably 20 μM or less, typically in the rangeof about 10 μM, 1 μM, 500 nM, 100 nM, 10 nM, 1 nM, or even lower. Asuitable assay that can be used is the assay described in Example 2,“Assay for Ramos B-Cell Line Stimulated with IL-4.” In certainimplementations, the active 2,4-pyrimidinediamine compounds have an IC₅₀of less than or equal to 5 μM, greater than 5 μM but less than 20 μM,greater than 20 μM, greater than 20 μM but less than 50 μM, or greaterthan 50 μM but less than 100 μM in the assay described in Example 2.

Additionally, the 2,4-pyrimidinediamine active compounds typicallyinhibit an activity of human primary T-cells with an IC₅₀ in the rangeof about 20 μM or less, typically in the range of about 10 μM, 1 μM, 500nM, 100 nM, 10 nM, 1 nM, or even lower. The IC₅₀ against human primaryT-cells can be determined in a standard in vitro assay with isolatedhuman primary T-cells. The active 2,4-pyrimidinediamine compoundstypically have an IC₅₀ of less than or equal to 5 μM, greater than 5 μMbut less than 20 μM, greater than 20 μM, or greater than 20 μM but lessthan 50 μM in the assay.

The 2,4-pyrimidinediamine active compounds typically also inhibitexpression of ICAM1 (CD54) induced by IFNγ exposure in U937 or A549cells with an IC₅₀ in the range of about 20 μM or less, typically in therange of about 10 μM, 1 μM, 500 nM, 100 nM, 10 nM, 1 nM, or even lower.The IC₅₀ against expression of ICAM (CD54) in IFNγ stimulated cells canbe determined in a functional cellular assay with an isolated A549 orU937 cell line. The active 2,4-pyrimidinediamine compounds typicallyhave an IC₅₀ of less than or equal to 20 μM, greater than 20 μM, orgreater than 20 μM but less than 50 μM in the assay.

E. Pharmaceutical Compositions of the Invention

Pharmaceutical compositions comprising the 2,4-pyrimidinediaminecompounds described herein (or prodrugs thereof) can be manufactured bymeans of conventional mixing, dissolving, granulating, dragee-makinglevigating, emulsifying, encapsulating, entrapping, or lyophilizationprocesses. The compositions can be formulated in conventional mannerusing one or more physiologically acceptable carriers, diluents,excipients, or auxiliaries which facilitate processing of the activecompounds into preparations which can be used pharmaceutically.

The 2,4-pyrimidinediamine compound or prodrug can be formulated in thepharmaceutical compositions per se, or in the form of a hydrate,solvate, N-oxide, or pharmaceutically acceptable salt, as describedherein. Typically, such salts are more soluble in aqueous solutions thanthe corresponding free acids and bases, but salts having lowersolubility than the corresponding free acids and bases may also beformed.

In one implementation, this invention provides a pharmaceuticalformulation comprising a compound selected from the compounds of theinvention, as described herein, or a prodrug thereof, and at least onepharmaceutically acceptable excipient, diluent, preservative,stabilizer, or mixture thereof.

In another implementation, the methods can be practiced as a therapeuticapproach towards the treatment of the conditions described herein. Thus,in a specific implementation, the 2,4-pyrimidinediamine compounds (andthe various forms described herein, including pharmaceuticalformulations comprising the compounds (in the various forms)) can beused to treat the conditions described herein in animal subjects,including humans. The methods generally comprise administering to thesubject an amount of a compound of the invention, or a salt, prodrug,hydrate, or N-oxide thereof, effective to treat the condition. In oneimplementation, the subject is a non-human mammal, including, but notlimited to, bovine, horse, feline, canine, rodent, or primate. Inanother implementation, the subject is a human.

The compounds can be provided in a variety of formulations and dosages.The compounds can be provided in a pharmaceutically acceptable form,including where the compound or prodrug can be formulated in thepharmaceutical compositions per se, or in the form of a hydrate,solvate, N-oxide, or pharmaceutically acceptable salt, as describedherein. Typically, such salts are more soluble in aqueous solutions thanthe corresponding free acids and bases, but salts having lowersolubility than the corresponding free acids and bases may also beformed. It is to be understood that reference to the compound,2,4-pyrimidinediamine compound, or “active” in discussions offormulations is also intended to include, where appropriate as known tothose of skill in the art, formulation of the prodrugs of the2,4-pyrimidinediamine compounds.

In one implementation, the compounds are provided as non-toxicpharmaceutically acceptable salts, as noted previously. Suitablepharmaceutically acceptable salts of the compounds of this inventioninclude acid addition salts such as those formed with hydrochloric acid,fumaric acid, p-toluenesulphonic acid, maleic acid, succinic acid,acetic acid, citric acid, tartaric acid, carbonic acid, or phosphoricacid. Salts of amine groups may also comprise quaternary ammonium saltsin which the amino nitrogen atom carries a suitable organic group suchas an alkyl, alkenyl, alkynyl, or substituted alkyl moiety. Furthermore,where the compounds of the invention carry an acidic moiety, suitablepharmaceutically acceptable salts thereof may include metal salts suchas alkali metal salts, e.g., sodium or potassium salts; and alkalineearth metal salts, e.g., calcium or magnesium salts.

The pharmaceutically acceptable salts of the present invention can beformed by conventional means, such as by reacting the free base form ofthe product with one or more equivalents of the appropriate acid in asolvent or medium in which the salt is insoluble or in a solvent such aswater which is removed in vacuo, by freeze drying, or by exchanging theanions of an existing salt for another anion on a suitable ion exchangeresin.

The present invention includes within its scope solvates of the2,4-pyrimidinediamine compounds and salts thereof, for example,hydrates.

The 2,4-pyrimidinediamine compounds may have one or more asymmetriccenters and may accordingly exist both as enantiomers and asdiastereoisomers. It is to be understood that all such isomers andmixtures thereof are encompassed within the scope of the presentinvention.

The 2,4-pyrimidinediamine compounds can be administered by oral,parenteral (e.g., intramuscular, intraperitoneal, intravenous, ICV,intracisternal injection or infusion, subcutaneous injection, orimplant), by inhalation spray nasal, vaginal, rectal, sublingual,urethral (e.g., urethral suppository) or topical routes ofadministration (e.g., gel, ointment, cream, aerosol, etc.) and can beformulated, alone or together, in suitable dosage unit formulationscontaining conventional non-toxic pharmaceutically acceptable carriers,adjuvants, excipients, and vehicles appropriate for each route ofadministration. In addition to the treatment of warm-blooded animalssuch as mice, rats, horses, cattle, sheep, dogs, cats, and monkeys, thecompounds of the invention can be effective in humans.

The pharmaceutical compositions for the administration of the2,4-pyrimidinediamine compounds can be conveniently presented in dosageunit form and can be prepared by any of the methods well known in theart of pharmacy. The pharmaceutical compositions can be, for example,prepared by uniformly and intimately bringing the active ingredient intoassociation with a liquid carrier, a finely divided solid carrier orboth, and then, if necessary, shaping the product into the desiredformulation. In the pharmaceutical composition the active objectcompound is included in an amount sufficient to produce the desiredtherapeutic effect. For example, pharmaceutical compositions of theinvention may take a form suitable for virtually any mode ofadministration, including, for example, topical, ocular, oral, buccal,systemic, nasal, injection, transdermal, rectal, and vaginal, or a formsuitable for administration by inhalation or insufflation.

For topical administration, the JAK-selective compound(s) or prodrug(s)can be formulated as solutions, gels, ointments, creams, suspensions,etc., as is well-known in the art.

Systemic formulations include those designed for administration byinjection (e.g., subcutaneous, intravenous, intramuscular, intrathecal,or intraperitoneal injection) as well as those designed for transdermal,transmucosal, oral, or pulmonary administration.

Useful injectable preparations include sterile suspensions, solutions,or emulsions of the active compound(s) in aqueous or oily vehicles. Thecompositions may also contain formulating agents, such as suspending,stabilizing, and/or dispersing agents. The formulations for injectioncan be presented in unit dosage form, e.g., in ampules or in multidosecontainers, and may contain added preservatives.

Alternatively, the injectable formulation can be provided in powder formfor reconstitution with a suitable vehicle, including but not limited tosterile pyrogen free water, buffer, and dextrose solution, before use.To this end, the active compound(s) can be dried by any art-knowntechnique, such as lyophilization, and reconstituted prior to use.

For transmucosal administration, penetrants appropriate to the barrierto be permeated are used in the formulation. Such penetrants are knownin the art.

For oral administration, the pharmaceutical compositions may take theform of, for example, lozenges, tablets, or capsules prepared byconventional means with pharmaceutically acceptable excipients such asbinding agents (e.g., pregelatinised maize starch, polyvinylpyrrolidone,or hydroxypropyl methylcellulose); fillers (e.g., lactose,microcrystalline cellulose, or calcium hydrogen phosphate); lubricants(e.g., magnesium stearate, talc, or silica); disintegrants (e.g., potatostarch or sodium starch glycolate); or wetting agents (e.g., sodiumlauryl sulfate). The tablets can be coated by methods well known in theart with, for example, sugars, films, or enteric coatings. Additionally,the pharmaceutical compositions containing the 2,4-substitutedpyrmidinediamine as active ingredient or prodrug thereof in a formsuitable for oral use may also include, for example, troches, lozenges,aqueous, or oily suspensions, dispersible powders or granules,emulsions, hard or soft capsules, or syrups or elixirs. Compositionsintended for oral use can be prepared according to any method known tothe art for the manufacture of pharmaceutical compositions, and suchcompositions may contain one or more agents selected from the groupconsisting of sweetening agents, flavoring agents, coloring agents, andpreserving agents in order to provide pharmaceutically elegant andpalatable preparations. Tablets contain the active ingredient (includingdrug and/or prodrug) in admixture with non-toxic pharmaceuticallyacceptable excipients which are suitable for the manufacture of tablets.These excipients can be for example, inert diluents, such as calciumcarbonate, sodium carbonate, lactose, calcium phosphate or sodiumphosphate; granulating and disintegrating agents (e.g., corn starch oralginic acid); binding agents (e.g. starch, gelatin, or acacia); andlubricating agents (e.g., magnesium stearate, stearic acid, or talc).The tablets can be left uncoated or they can be coated by knowntechniques to delay disintegration and absorption in thegastrointestinal tract and thereby provide a sustained action over alonger period. For example, a time delay material such as glycerylmonostearate or glyceryl distearate can be employed. They may also becoated by the techniques described in the U.S. Pat. Nos. 4,256,108;4,166,452; and 4,265,874 to form osmotic therapeutic tablets for controlrelease. The pharmaceutical compositions of the invention may also be inthe form of oil-in-water emulsions.

Liquid preparations for oral administration may take the form of, forexample, elixirs, solutions, syrups, or suspensions, or they can bepresented as a dry product for constitution with water or other suitablevehicle before use. Such liquid preparations can be prepared byconventional means with pharmaceutically acceptable additives such assuspending agents (e.g., sorbitol syrup, cellulose derivatives, orhydrogenated edible fats); emulsifying agents (e.g., lecithin, oracacia); non-aqueous vehicles (e.g., almond oil, oily esters, ethylalcohol, Cremophore™, or fractionated vegetable oils); and preservatives(e.g., methyl or propyl-p-hydroxybenzoates or sorbic acid). Thepreparations may also contain buffer salts, preservatives, flavoring,coloring, and sweetening agents as appropriate.

Preparations for oral administration can be suitably formulated to givecontrolled release of the active compound or prodrug, as is well known.

For buccal administration, the compositions may take the form of tabletsor lozenges formulated in the conventional manner.

For rectal and vaginal routes of administration, the active compound(s)can be formulated as solutions (for retention enemas), suppositories, orointments containing conventional suppository bases such as cocoa butteror other glycerides.

For nasal administration or administration by inhalation orinsufflation, the active compound(s) or prodrug(s) can be convenientlydelivered in the form of an aerosol spray from pressurized packs or anebulizer with the use of a suitable propellant (e.g.,dichlorodifluoromethane, trichlorofluoromethane,dichlorotetrafluoroethane, fluorocarbons, carbon dioxide, or othersuitable gas). In the case of a pressurized aerosol, the dosage unit canbe determined by providing a valve to deliver a metered amount. Capsulesand cartridges for use in an inhaler or insufflator (for example,capsules and cartridges comprised of gelatin) can be formulatedcontaining a powder mix of the compound and a suitable powder base suchas lactose or starch.

The pharmaceutical compositions can be in the form of a sterileinjectable aqueous or oleaginous suspension. This suspension can beformulated according to the known art using those suitable dispersing orwetting agents and suspending agents which have been mentioned above.The sterile injectable preparation may also be a sterile injectablesolution or suspension in a non-toxic parenterally-acceptable diluent orsolvent. Among the acceptable vehicles and solvents that can be employedare water, Ringer's solution, and isotonic sodium chloride solution. The2,4-pyrimidinediamine compounds may also be administered in the form ofsuppositories for rectal or urethral administration of the drug. Inparticular implementations, the compounds can be formulated as urethralsuppositories, for example, for use in the treatment of fertilityconditions, particularly in males (e.g., for the treatment of testiculardysfunction).

According to the invention, 2,4-pyrimidinediamine compounds can be usedfor manufacturing a composition or medicament, including medicamentssuitable for rectal or urethral administration. The invention alsorelates to methods for manufacturing compositions including2,4-pyrimidinediamine compounds in a form that is suitable for urethralor rectal administration, including suppositories.

For topical use, creams, ointments, jellies, gels, solutions,suspensions, etc., containing the 2,4-pyrimidinediamine compounds can beemployed. In certain implementations, the 2,4-pyrimidinediaminecompounds can be formulated for topical administration with polyethyleneglycol (PEG). These formulations may optionally comprise additionalpharmaceutically acceptable ingredients such as diluents, stabilizers,and/or adjuvants. In particular implementations, the topicalformulations are formulated for the treatment of allergic conditionsand/or skin conditions including psoriasis, contact dermatitis, andatopic dermatitis, among others described herein.

According to the invention, 2,4-pyrimidinediamine compounds can be usedfor manufacturing a composition or medicament, including medicamentssuitable for topical administration. The invention also relates tomethods for manufacturing compositions including 2,4-pyrimidinediaminecompounds in a form that is suitable for topical administration.

According to the present invention, 2,4-pyrimidinediamine compounds canalso be delivered by any of a variety of inhalation devices and methodsknown in the art, including, for example: U.S. Pat. No. 6,241,969; U.S.Pat. No. 6,060,069; U.S. Pat. No. 6,238,647; U.S. Pat. No. 6,335,316;U.S. Pat. No. 5,364,838; U.S. Pat. No. 5,672,581; WO96/32149;WO95/24183; U.S. Pat. No. 5,654,007; U.S. Pat. No. 5,404,871; U.S. Pat.No. 5,672,581; U.S. Pat. No. 5,743,250; U.S. Pat. No. 5,419,315; U.S.Pat. No. 5,558,085; WO98/33480; U.S. Pat. No. 5,364,833; U.S. Pat. No.5,320,094; U.S. Pat. No. 5,780,014; U.S. Pat. Nos. 5,658,878; 5,518,998;5,506,203; U.S. Pat. No. 5,661,130; U.S. Pat. No. 5,655,523; U.S. Pat.No. 5,645,051; U.S. Pat. No. 5,622,166; U.S. Pat. No. 5,577,497; U.S.Pat. No. 5,492,112; U.S. Pat. No. 5,327,883; U.S. Pat. No. 5,277,195;U.S. Pat. App. No. 20010041190; U.S. Pat. App. No. 20020006901; and U.S.Pat. App. No. 20020034477.

Included among the devices which can be used to administer particularexamples of the 2,4-pyrimidinediamine compounds are those well-known inthe art, such as metered dose inhalers, liquid nebulizers, dry powderinhalers, sprayers, thermal vaporizers, and the like. Other suitabletechnology for administration of particular 2,4-pyrimidinediaminecompounds includes electrohydrodynamic aerosolizers.

In addition, the inhalation device is preferably practical, in the senseof being easy to use, small enough to carry conveniently, capable ofproviding multiple doses, and durable. Some specific examples ofcommercially available inhalation devices are Turbohaler (Astra,Wilmington, Del.), Rotahaler (Glaxo, Research Triangle Park, N.C.),Diskus (Glaxo, Research Triangle Park, N.C.), the Ultravent nebulizer(Mallinckrodt), the Acorn II nebulizer (Marquest Medical Products,Totowa, N.J.) the Ventolin metered dose inhaler (Glaxo, ResearchTriangle Park, N.C.), and the like. In one implementation,2,4-pyrimidinediamine compounds can be delivered by a dry powder inhaleror a sprayer.

As those skilled in the art will recognize, the formulation of2,4-pyrimidinediamine compounds, the quantity of the formulationdelivered, and the duration of administration of a single dose depend onthe type of inhalation device employed as well as other factors. Forsome aerosol delivery systems, such as nebulizers, the frequency ofadministration and length of time for which the system is activated willdepend mainly on the concentration of 2,4-pyrimidinediamine compounds inthe aerosol. For example, shorter periods of administration can be usedat higher concentrations of 2,4-pyrimidinediamine compounds in thenebulizer solution. Devices such as metered dose inhalers can producehigher aerosol concentrations and can be operated for shorter periods todeliver the desired amount of 2,4-pyrimidinediamine compounds in someimplementations. Devices such as dry powder inhalers deliver activeagent until a given charge of agent is expelled from the device. In thistype of inhaler, the amount of 2,4-pyrimidinediamine compounds in agiven quantity of the powder determines the dose delivered in a singleadministration. The formulation of 2,4-pyrimidinediamine is selected toyield the desired particle size in the chosen inhalation device.

Formulations of 2,4-pyrimidinediamine compounds for administration froma dry powder inhaler may typically include a finely divided dry powdercontaining 2,4-pyrimidinediamine compounds, but the powder can alsoinclude a bulking agent, buffer, carrier, excipient, another additive,or the like. Additives can be included in a dry powder formulation of2,4-pyrimidinediamine compounds, for example, to dilute the powder asrequired for delivery from the particular powder inhaler, to facilitateprocessing of the formulation, to provide advantageous powder propertiesto the formulation, to facilitate dispersion of the powder from theinhalation device, to stabilize to the formulation (e.g., antioxidantsor buffers), to provide taste to the formulation, or the like. Typicaladditives include mono-, di-, and polysaccharides; sugar alcohols andother polyols, such as, for example, lactose, glucose, raffinose,melezitose, lactitol, maltitol, trehalose, sucrose, mannitol, starch, orcombinations thereof; surfactants, such as sorbitols, diphosphatidylcholine, or lecithin; and the like.

The present invention also relates to a pharmaceutical compositionincluding 2,4-pyrimidinediamine compounds suitable for administration byinhalation. According to the invention, 2,4-pyrimidinediamine compoundscan be used for manufacturing a composition or medicament, includingmedicaments suitable for administration by inhalation. The inventionalso relates to methods for manufacturing compositions including2,4-pyrimidinediamine compounds in a form that is suitable foradministration, including administration by inhalation. For example, adry powder formulation can be manufactured in several ways, usingconventional techniques, such as described in any of the publicationsmentioned above and incorporated expressly herein by reference, and, forexample, Baker, et al., U.S. Pat. No. 5,700,904, the entire disclosureof which is incorporated expressly herein by reference. Particles in thesize range appropriate for maximal deposition in the lower respiratorytract can be made by micronizing, milling, or the like. And a liquidformulation can be manufactured by dissolving the 2,4-pyrimidinediaminecompounds in a suitable solvent, such as water, at an appropriate pH,including buffers or other excipients.

Pharmaceutical compositions comprising the 2,4-pyrimidinediaminecompounds described herein (or prodrugs thereof) can be manufactured bymeans of conventional mixing, dissolving, granulating, dragee-makinglevigating, emulsifying, encapsulating, entrapping, or lyophilizationprocesses. The compositions can be formulated in conventional mannerusing one or more physiologically acceptable carriers, diluents,excipients, or auxiliaries which facilitate processing of the activecompounds into preparations which can be used pharmaceutically.

For ocular administration, the 2,4-pyrimidinediamine compound(s) orprodrug(s) can be formulated as a solution, emulsion, suspension, etc.,suitable for administration to the eye. A variety of vehicles suitablefor administering compounds to the eye are known in the art. Specificnon-limiting examples are described in U.S. Pat. No. 6,261,547; U.S.Pat. No. 6,197,934; U.S. Pat. No. 6,056,950; U.S. Pat. No. 5,800,807;U.S. Pat. No. 5,776,445; U.S. Pat. No. 5,698,219; U.S. Pat. No.5,521,222; U.S. Pat. No. 5,403,841; U.S. Pat. No. 5,077,033; U.S. Pat.No. 4,882,150; and U.S. Pat. No. 4,738,851.

For prolonged delivery, the 2,4-pyrimidinediamine compound(s) orprodrug(s) can be formulated as a depot preparation for administrationby implantation or intramuscular injection. The active ingredient can beformulated with suitable polymeric or hydrophobic materials (e.g., as anemulsion in an acceptable oil) or ion exchange resins, or as sparinglysoluble derivatives (e.g., as a sparingly soluble salt). Alternatively,transdermal delivery systems manufactured as an adhesive disc or patchwhich slowly releases the active compound(s) for percutaneous absorptioncan be used. To this end, permeation enhancers can be used to facilitatetransdermal penetration of the active compound(s). Suitable transdermalpatches are described in, for example, U.S. Pat. No. 5,407,713; U.S.Pat. No. 5,352,456; U.S. Pat. No. 5,332,213; U.S. Pat. No. 5,336,168;U.S. Pat. No. 5,290,561; U.S. Pat. No. 5,254,346; U.S. Pat. No.5,164,189; U.S. Pat. No. 5,163,899; U.S. Pat. No. 5,088,977; U.S. Pat.No. 5,087,240; U.S. Pat. No. 5,008,110; and U.S. Pat. No. 4,921,475.

Alternatively, other pharmaceutical delivery systems can be employed.Liposomes and emulsions are well-known examples of delivery vehiclesthat can be used to deliver active compound(s) or prodrug(s). Certainorganic solvents such as dimethylsulfoxide (DMSO) may also be employed,although usually at the cost of greater toxicity.

The pharmaceutical compositions may, if desired, be presented in a packor dispenser device which may contain one or more unit dosage formscontaining the active compound(s). The pack may, for example, comprisemetal or plastic foil, such as a blister pack. The pack or dispenserdevice can be accompanied by instructions for administration.

The 2,4-pyrimidinediamine compound(s) or prodrug(s) described herein, orcompositions thereof, will generally be used in an amount effective toachieve the intended result, for example, in an amount effective totreat or prevent the particular condition being treated. The compound(s)can be administered therapeutically to achieve therapeutic benefit orprophylactically to achieve prophylactic benefit. By therapeutic benefitis meant eradication or amelioration of the underlying disorder beingtreated and/or eradication or amelioration of one or more of thesymptoms associated with the underlying disorder such that the patientreports an improvement in feeling or condition, notwithstanding that thepatient may still be afflicted with the underlying disorder. Forexample, administration of a compound to a patient suffering from anallergy provides therapeutic benefit not only when the underlyingallergic response is eradicated or ameliorated, but also when thepatient reports a decrease in the severity or duration of the symptomsassociated with the allergy following exposure to the allergen. Asanother example, therapeutic benefit in the context of asthma includesan improvement in respiration following the onset of an asthmatic attackor a reduction in the frequency or severity of asthmatic episodes. Asanother specific example, therapeutic benefit in the context oftransplantation rejection includes the ability to alleviate an acuterejection episode, such as, for example, HVGR or GVHR, or the ability toprolong the time period between onset of acute rejection episodes and/oronset of chronic rejection. Therapeutic benefit also includes halting orslowing the progression of the disease, regardless of whetherimprovement is realized.

The amount of compound administered will depend upon a variety offactors, including, for example, the particular condition being treated,the mode of administration, the severity of the condition being treated,the age and weight of the patient, the bioavailability of the particularactive compound. Determination of an effective dosage is well within thecapabilities of those skilled in the art.

As known by those of skill in the art, the preferred dosage of2,4-pyrimidinediamine compounds will also depend on the age, weight,general health, and severity of the condition of the individual beingtreated. Dosage may also need to be tailored to the sex of theindividual and/or the lung capacity of the individual, whereadministered by inhalation. Dosage may also be tailored to individualssuffering from more than one condition or those individuals who haveadditional conditions which affect lung capacity and the ability tobreathe normally, for example, emphysema, bronchitis, pneumonia, andrespiratory infections. Dosage, and frequency of administration of thecompounds or prodrugs thereof, will also depend on whether the compoundsare formulated for treatment of acute episodes of a condition or for theprophylactic treatment of a disorder. For example, acute episodes ofallergic conditions, including allergy-related asthma, transplantrejection, etc. A skilled practitioner will be able to determine theoptimal dose for a particular individual.

For prophylactic administration, the compound can be administered to apatient at risk of developing one of the previously describedconditions. For example, if it is unknown whether a patient is allergicto a particular drug, the compound can be administered prior toadministration of the drug to avoid or ameliorate an allergic responseto the drug. Alternatively, prophylactic administration can be appliedto avoid the onset of symptoms in a patient diagnosed with theunderlying disorder. For example, a compound can be administered to anallergy sufferer prior to expected exposure to the allergen. Compoundsmay also be administered prophylactically to healthy individuals who arerepeatedly exposed to agents known to one of the above-describedmaladies to prevent the onset of the disorder. For example, a compoundcan be administered to a healthy individual who is repeatedly exposed toan allergen known to induce allergies, such as latex, in an effort toprevent the individual from developing an allergy. Alternatively, acompound can be administered to a patient suffering from asthma prior topartaking in activities which trigger asthma attacks to lessen theseverity of, or avoid altogether, an asthmatic episode.

In the context of transplant rejection, the compound can be administeredwhile the patient is not having an acute rejection reaction to avoid theonset of rejection and/or prior to the appearance of clinicalindications of chronic rejection. The compound can be administeredsystemically to the patient as well as administered to the tissue ororgan prior to transplanting the tissue or organ in the patient.

The amount of compound administered will depend upon a variety offactors, including, for example, the particular indication beingtreated, the mode of administration, whether the desired benefit isprophylactic or therapeutic, the severity of the indication beingtreated and the age and weight of the patient, and the bioavailabilityof the particular active compound. Determination of an effective dosageis well within the capabilities of those skilled in the art.

Effective dosages can be estimated initially from in vitro assays. Forexample, an initial dosage for use in animals can be formulated toachieve a circulating blood or serum concentration of active compoundthat is at or above an IC₅₀ of the particular compound as measured in asin vitro assay. Calculating dosages to achieve such circulating blood orserum concentrations taking into account the bioavailability of theparticular compound is well within the capabilities of skilled artisans.For guidance, the reader is referred to Fingl & Woodbury, “GeneralPrinciples,” In: Goodman and Gilman's The Pharmaceutical Basis ofTherapeutics, Chapter 1, pp. 1-46, latest edition, Pergamagon Press, andthe references cited therein.

Initial dosages can also be estimated from in vivo data, such as animalmodels. Animal models useful for testing the efficacy of compounds totreat or prevent the various diseases described above are well-known inthe art. Suitable animal models of hypersensitivity or allergicreactions are described in Foster, (1995) Allergy 50(21 Suppl):6-9,discussion 34-38 and Tumas et al., (2001), J. Allergy Clin. Immunol.107(6):1025-1033. Suitable animal models of allergic rhinitis aredescribed in Szelenyi et al., (2000), Arzneimittelforschung50(11):1037-42; Kawaguchi et al., (1994), Clin. Exp. Allergy24(3):238-244 and Sugimoto et al., (2000), Immunopharmacology 48(1):1-7.Suitable animal models of allergic conjunctivitis are described inCarreras et al., (1993), Br. J. Ophthalmol. 77(8):509-514; Saiga et al.,(1992), Ophthalmic Res. 24(1):45-50; and Kunert et al., (2001), Invest.Ophthalmol. Vis. Sci. 42(11):2483-2489. Suitable animal models ofsystemic mastocytosis are described in O'Keefe et al., (1987), J. Vet.Intern. Med. 1(2):75-80 and Bean-Knudsen et al., (1989), Vet. Pathol.26(1):90-92. Suitable animal models of hyper IgE syndrome are describedin Claman et al., (1990), Clin. Immunol. Immunopathol. 56(1):46-53.Suitable animal models of B-cell lymphoma are described in Hough et al.,(1998), Proc. Natl. Acad. Sci. USA 95:13853-13858 and Hakim et al.,(1996), J. Immunol. 157(12):5503-5511. Suitable animal models of atopicdisorders such as atopic dermatitis, atopic eczema, and atopic asthmaare described in Chan et al., (2001), J. Invest. Dermatol.117(4):977-983 and Suto et al., (1999), Int. Arch. Allergy Immunol.120(Suppl 1):70-75. Suitable animal models of transplant rejection, suchas models of HVGR, are described in O'Shea et al., (2004), NatureReviews Drug Discovery 3:555-564; Cetkovic-Curlje & Tibbles, (2004),Current Pharmaceutical Design 10:1767-1784; and Chengelian et al.,(2003), Science 302:875-878. Ordinarily skilled artisans can routinelyadapt such information to determine dosages suitable for humanadministration.

Dosage amounts will typically be in the range of from about 0.0001 or0.001 or 0.01 mg/kg/day to about 100 mg/kg/day, but can be higher orlower, depending upon, among other factors, the activity of thecompound, its bioavailability, the mode of administration, and variousfactors discussed above. Dosage amount and interval can be adjustedindividually to provide plasma levels of the compound(s) which aresufficient to maintain therapeutic or prophylactic effect. For example,the compounds can be administered once per week, several times per week(e.g., every other day), once per day, or multiple times per day,depending upon, among other things, the mode of administration, thespecific indication being treated, and the judgment of the prescribingphysician. In cases of local administration or selective uptake, such aslocal topical administration, the effective local concentration ofactive compound(s) may not be related to plasma concentration. Skilledartisans will be able to optimize effective local dosages without undueexperimentation.

Preferably, the compound(s) will provide therapeutic or prophylacticbenefit without causing substantial toxicity. Toxicity of thecompound(s) can be determined using standard pharmaceutical procedures.The dose ratio between toxic and therapeutic (or prophylactic) effect isthe therapeutic index. Compounds(s) that exhibit high therapeuticindices are preferred.

The foregoing disclosure pertaining to the dosage requirements for the2,4-substituted pyrimidinediamine compounds is pertinent to dosagesrequired for prodrugs, with the realization, apparent to the skilledartisan, that the amount of prodrug(s) administered will also dependupon a variety of factors, including, for example, the bioavailabilityof the particular prodrug(s) and the conversation rate and efficiencyinto active drug compound under the selected route of administration.Determination of an effective dosage of prodrug(s) for a particular useand mode of administration is well within the capabilities of thoseskilled in the art.

Effective dosages can be estimated initially from in vitro activity andmetabolism assays. For example, an initial dosage of prodrug for use inanimals can be formulated to achieve a circulating blood or serumconcentration of the metabolite active compound that is at or above anIC₅₀ of the particular compound as measured in as in vitro assay, suchas the in vitro CHMC or BMMC and other in vitro assays described in U.S.Patent Application Publication No. 2004/0029902, internationalapplication Serial No. PCT/US03/03022 filed Jan. 31, 2003 (WO03/063794), U.S. application Ser. No. 10/631,029 filed Jul. 29, 2003,international application Serial No. PCT/US03/24087 (WO2004/014382),U.S. Patent Application Publication No. 2005/0234049, and internationalapplication Serial No. PCT/US2004/24716 (WO005/016893). Calculatingdosages to achieve such circulating blood or serum concentrations,taking into account the bioavailability of the particular prodrug viathe desired route of administration, is well within the capabilities ofskilled artisans. For guidance, the reader is referred to Fingl &Woodbury, “General Principles,” In: Goodman and Gilman's ThePharmaceutical Basis of Therapeutics, Chapter 1, pp. 1-46, latestedition, Pagamonon Press, and the references cited therein.

Also provided are kits for administration of the 2,4-pyrimidinediamine,prodrug thereof, or pharmaceutical formulations comprising the compoundthat may include a dosage amount of at least one 2,4-pyrimidinediamineor a composition comprising at least one 2,4-pyrimidinediamine, asdisclosed herein. Kits may further comprise suitable packaging and/orinstructions for use of the compound. Kits may also comprise a means forthe delivery of the at least one 2,4-pyrimidinediamine or compositionscomprising at least one 2,4-pyrimidinediamine, such as an inhaler, spraydispenser (e.g., nasal spray), syringe for injection, or pressure packfor capsules, tables, suppositories, or other device as describedherein.

Additionally, the compounds of the present invention can be assembled inthe form of kits. The kit provides the compound and reagents to preparea composition for administration. The composition can be in a dry orlyophilized form or in a solution, particularly a sterile solution. Whenthe composition is in a dry form, the reagent may comprise apharmaceutically acceptable diluent for preparing a liquid formulation.The kit may contain a device for administration or for dispensing thecompositions, including, but not limited to, syringe, pipette,transdermal patch, or inhalant.

The kits may include other therapeutic compounds for use in conjunctionwith the compounds described herein. In one implementation, thetherapeutic agents are immunosuppressant or anti-allergen compounds.These compounds can be provided in a separate form or mixed with thecompounds of the present invention.

The kits will include appropriate instructions for preparation andadministration of the composition, side effects of the compositions, andany other relevant information. The instructions can be in any suitableformat, including, but not limited to, printed matter, videotape,computer readable disk, or optical disc.

In one implementation, this invention provides a kit comprising acompound selected from the compounds of the invention or a prodrugthereof, packaging, and instructions for use.

In another implementation, this invention provides a kit comprising thepharmaceutical formulation comprising a compound selected from thecompounds of the invention or a prodrug thereof and at least onepharmaceutically acceptable excipient, diluent, preservative,stabilizer, or mixture thereof, packaging, and instructions for use.

In another aspect of the invention, kits for treating an individual whosuffers from or is susceptible to the conditions described herein areprovided, comprising a container comprising a dosage amount of an2,4-pyrimidinediamine or composition, as disclosed herein, andinstructions for use. The container can be any of those known in the artand appropriate for storage and delivery of oral, intravenous, topical,rectal, urethral, or inhaled formulations.

Kits may also be provided that contain sufficient dosages of the2,4-pyrimidinediamine or composition to provide effective treatment foran individual for an extended period, such as a week, 2 weeks, 3, weeks,4 weeks, 6 weeks, or 8 weeks or more.

F. General Synthesis of the Compounds of the Invention

The 2,4-pyrimidinediamine compounds and prodrugs of the invention can besynthesized via a variety of different synthetic routes usingcommercially available starting materials and/or starting materialsprepared by conventional synthetic methods. Suitable exemplary methodsthat can be routinely adapted to synthesize the 2,4-pyrimidinediaminecompounds and prodrugs of the invention are found in U.S. Pat. No.5,958,935, the disclosure of which is incorporated herein by reference.Specific examples describing the synthesis of numerous2,4-pyrimidinediamine compounds and prodrugs, as well as intermediatesthereof, are described in copending U.S. Patent Application PublicationNo. US2004/0029902A1, the contents of which are incorporated herein byreference. Suitable exemplary methods that can be routinely used and/oradapted to synthesize active 2,4-pyrimidinediamine compounds can also befound in international application Serial No. PCT/US03/03022 filed Jan.31, 2003 (WO 03/063794), U.S. application Ser. No. 10/631,029 filed Jul.29, 2003, international application Serial No. PCT/US03/24087(WO2004/014382), U.S. Patent Application Publication No. 2005/0234049,and international application Serial No. PCT/US2004/24716(WO005/016893), the disclosures of which are incorporated herein byreference. All of the compounds described herein (including prodrugs)can be prepared by routine adaptation of these methods.

Specific exemplary synthetic methods for the 2,4-pyrimidinediaminesdescribed herein are also described in Example 1 below. Those of skillin the art will also be able to readily adapt these examples for thesynthesis of additional 2,4-pyrimidinediamines as described herein.

A variety of exemplary synthetic routes that can be used to synthesizethe 2,4-pyrimidinediamine compounds of the invention are described inSchemes (I)-(VII), below. These methods can be routinely adapted tosynthesize the 2,4-pyrimidinediamine compounds and prodrugs describedherein.

In one exemplary implementation, the compounds can be synthesized fromsubstituted or unsubstituted uracils as illustrated in Scheme (I),below:

In Scheme (I), ring A, ring B, R¹, R², R³, X, W, p, and q are as definedherein. According to Scheme (I), uracil A-1 is dihalogenated at the 2-and 4-positions using a standard halogenating agent such as POCl₃ (orother standard halogenating agent) under standard conditions to yield2,4-dichloropyrimidine A-2. Depending upon the X substituent, inpyrimidinediamine A-2, the chloride at the C4 position is more reactivetowards nucleophiles than the chloride at the C2 position. Thisdifferential reactivity can be exploited to synthesize2,4-pyrimidinediamines I by reacting 2,4-dichloropyrimidine A-2 firstwith one equivalent of amine A-3, yielding4N-substituted-2-chloro-4-pyrimidineamine A-4, and then with amine A-5,yielding a 2,4-pyrimidinediamine derivative A-6, where N2 nitrogen canbe selectively alkylated to give compounds of formula I.

Typically, the C4 halide is more reactive towards nucleophiles, asillustrated in Scheme (I). However, as will be recognized by skilledartisans, the identity of the X substituent may alter this reactivity.For example, when X is trifluoromethyl, a 50:50 mixture of4N-substituted-4-pyrimidineamine A-4 and the corresponding2N-substituted-2-pyrimidineamine is obtained. The regioselectivity ofthe reaction can also be controlled by adjusting the solvent and othersynthetic conditions (such as temperature), as is well-known in the art.

The reactions depicted in Scheme (I) may proceed more quickly when thereaction mixtures are heated via microwave. When heating in thisfashion, the following conditions can be used: heat to 175° C. inethanol for 5-20 min. in a Smith Reactor (Personal Chemistry, Uppsala,Sweden) in a sealed tube (at 20 bar pressure).

The uracil A-1 starting materials can be purchased from commercialsources or prepared using standard techniques of organic chemistry.Commercially available uracils that can be used as starting materials inScheme (I) include, by way of example and not limitation, uracil(Aldrich #13,078-8; CAS Registry 66-22-8); 5-bromouracil (Aldrich#85,247-3; CAS Registry 51-20-7; 5-fluorouracil (Aldrich #85,847-1; CASRegistry 51-21-8); 5-iodouracil (Aldrich #85,785-8; CAS Registry696-07-1); 5-nitrouracil (Aldrich #85,276-7; CAS Registry 611-08-5); and5-(trifluoromethyl)-uracil (Aldrich #22,327-1; CAS Registry 54-20-6).Additional 5-substituted uracils are available from GeneralIntermediates of Canada, Inc., Edmonton, Calif., and/or Interchim,Cedex, France, or can be prepared using standard techniques. Myriadtextbook references teaching suitable synthetic methods are providedinfra.

Amines A-3 and A-5 can be purchased from commercial sources or,alternatively, can be synthesized using standard techniques. Forexample, suitable amines can be synthesized from nitro precursors usingstandard chemistry. Specific exemplary reactions are provided in theExamples section. See also Vogel, 1989, Practical Organic Chemistry,Addison Wesley Longman, Ltd. and John Wiley & Sons, Inc.

Skilled artisans will recognize that in some instances, amines A-3 andA-5 and/or substituent X on uracil A-1 may include functional groupsthat require protection during synthesis. The exact identity of anyprotecting group(s) used will depend upon the identity of the functionalgroup being protected, and will be apparent to those of skill in theart. Guidance for selecting appropriate protecting groups, as well assynthetic strategies for their attachment and removal, can be found, forexample, in Greene & Wuts, Protective Groups in Organic Synthesis, 3dEdition, John Wiley & Sons, Inc., New York (1999) and the referencescited therein (hereinafter “Greene & Wuts”).

Thus, “protecting group” refers to a group of atoms that, when attachedto a reactive functional group in a molecule, mask, reduce or preventthe reactivity of the functional group. Typically, a protecting groupcan be selectively removed as desired during the course of a synthesis.Examples of protecting groups can be found in Greene and Wuts, asmentioned above, and, additionally, in Harrison et al., Compendium ofSynthetic Organic Methods, Vols. 1-8, 1971-1996, John Wiley & Sons, NY.Representative amino protecting groups include, but are not limited to,formyl, acetyl, trifluoroacetyl, benzyl, benzyloxycarbonyl (“CBZ”),tert-butoxycarbonyl (“Boc”), trimethylsilyl (“TMS”),2-trimethylsilyl-ethanesulfonyl (“TES”), trityl and substituted tritylgroups, allyloxycarbonyl, 9-fluorenylmethyloxycarbonyl (“FMOC”),nitro-veratryloxycarbonyl (“NVOC”), and the like. Representativehydroxyl protecting groups include, but are not limited to, those wherethe hydroxyl group is either acylated to form acetate and benzoateesters or alkylated to form benzyl and trityl ethers, as well as alkylethers, tetrahydropyranyl ethers, trialkylsilyl ethers (e.g., TMS orTIPPS groups), aryl silyl ethers (e.g., triphenylsilyl ether), mixedalkyl and aryl substituted silyl ethers, and allyl ethers.

A specific implementation of Scheme (I) utilizing 5-fluorouracil(Aldrich #32,937-1) as a starting material is illustrated in Scheme(Ia), below:

In Scheme (Ia), ring A, ring B, R², R³, W, p, and q are as previouslydefined for Scheme (I). Asymmetric2N,4N-disubstituted-5-fluoro-2,4-pyrimidinediamine A-10 can be obtainedby reacting 2,4-dichloro-5-fluoropyrimidine A-8 with one equivalent ofamine A-3 (to yield 2-chloro-N4-substituted-5-fluoro-4-pyrimidineamineA-9) followed by one or more equivalents of amine A-5.

In another exemplary implementation, the 2,4-pyrimidinediamine compoundsof the invention can be synthesized from substituted or unsubstitutedcytosines as illustrated in Schemes (IIa) and (IIb), below:

In Schemes (IIa) and (IIb), ring A, ring B, R², R³, X, W, p, and q areas previously defined for Scheme (I) and PG represents a protectinggroup. Referring to Scheme (IIa), the C4 exocyclic amine of cytosineA-11 is first protected with a suitable protecting group PG to yieldN4-protected cytosine A-12. For specific guidance regarding protectinggroups useful in this context, see Vorbrüggen and Ruh-Pohlenz, 2001,Handbook of Nucleoside Synthesis, John Wiley & Sons, NY, pp. 1-631(“Vorbrüggen”). Protected cytosine A-12 is halogenated at the C2position using a standard halogenation reagent under standard conditionsto yield 2-chloro-4N-protected-4-pyrimidineamine A-13. Reaction withamine A-5 gives A-14, which, on deprotection of the C4 exocyclic amine,gives A-15. Reaction of A-15 with electrophile A-16 yields2,4-pyrimidinediamine derivative A-6.

Alternatively, referring to Scheme (IIb), cytosine A-11 can be reactedwith electrophile A-16 or A-18 to yield N4-substituted cytosine A-17 orA-19, respectively. The substituted cytosines A-17 may then behalogenated as previously described, and reacted with amine A-5 to yielda 2,4-pyrimidinediamine A-6. In the case of N-4 substituted cytosineA-19, the cytosines may be halogenated as previously described, reactedwith amine A-5, and then deprotected to yield a 2,4-pyrimidinediamineA-6.

Commercially-available cytosines that can be used as starting materialsin Schemes (IIa) and (IIb) include, but are not limited to, cytosine(Aldrich #14,201-8; CAS Registry 71-30-7); N⁴-acetylcytosine (Aldrich#37,791-0; CAS Registry 14631-20-0); 5-fluorocytosine (Aldrich#27,159-4; CAS Registry 2022-85-7); and 5-(trifluoromethyl)-cytosine.Other suitable cytosines useful as starting materials in Schemes (IIa)are available from General Intermediates of Canada, Inc., Edmonton,Calif., and/or Interchim, Cedex, France, or can be prepared usingstandard techniques. Myriad textbook references teaching suitablesynthetic methods are provided infra.

In still another exemplary implementation, the 2,4-pyrimidinediaminecompounds of the invention can be synthesized from substituted orunsubstituted 2-amino-4-pyrimidinols as illustrated in Scheme (III),below:

In Scheme (III), ring A, ring B, R², R³, X, W, p, and q are aspreviously defined for Scheme (I) and LG is a leaving group as discussedin more detail in connection with Scheme IV, infra. Referring to Scheme(III), 2-amino-4-pyrimidinol A-21 is reacted with arylating agent A-22to yield N2-substituted-4-pyrimidinol A-23, which is then halogenated aspreviously described to yield N2-substituted-4-halo-2-pyrimidineamineA-24. Further reaction with amine A-3 affords a 2,4-pyrimidinediaminederivative A-6.

Suitable commercially-available 2-amino-4-pyrimidinols A-21 that can beused as starting materials in Scheme (III) are available from GeneralIntermediates of Canada, Inc., Edmonton, Calif., and/or Interchim,Cedex, France, or can be prepared using standard techniques. Myriadtextbook references teaching suitable synthetic methods are providedinfra.

Alternatively, the 2,4-pyrimidinediamine compounds of the invention canbe prepared from substituted or unsubstituted 4-amino-2-pyrimidinols asillustrated in Scheme (IV), below:

In Scheme (IV), ring A, ring B, R², R³, X, W, p, and q are as previouslydefined for Scheme (I). Referring to Scheme (IV), the C2-hydroxyl of4-amino-2-pyrimidinol A-25 is more reactive towards nucleophiles thanthe C4-amino such that reaction with amine A-5 yieldsN2-substituted-2,4-pyrimidinediamine A-15. Subsequent reaction withcompound A-16, which includes a suitable leaving group, yields a2,4-pyrimidinediamine derivative A-6. Compound A-16 may includevirtually any leaving group that can be displaced by the C4-amino ofN2-substituted-2,4-pyrimidinediamine A-15. Suitable leaving groupsinclude, but are not limited to, halogens, methanesulfonyloxy (mesyloxy;“OMs”), trifluoromethanesulfonyloxy (“OTf”) and p-toluenesulfonyloxy(tosyloxy; “OTs”), benzene sulfonyloxy (“besylate”) and m-nitro benzenesulfonyloxy (“nosylate”). Other suitable leaving groups will be apparentto those of skill in the art.

Substituted 4-amino-2-pyrimidinol starting materials can be obtainedcommercially or synthesized using standard techniques. Myriad textbookreferences teaching suitable synthetic methods are provided infra.

In still another exemplary implementation, the 2,4-pyrimidinediaminecompounds of the invention can be prepared from2-chloro-4-aminopyrimidines or 2-amino-4-chloropyrimidines asillustrated in Scheme (V), below:

In Scheme (V), ring A, ring B, R², R³, X, W, p, and q are as defined forScheme (I) and leaving group is as defined for Scheme (IV). Referring toScheme (V), 2-amino-4-chloropyrimidine A-26 is reacted with amine A-3 toyield 4N-substituted-2,4-pyrimidinediamine A-27, which, followingreaction with compound A-22, yields a N2,N4-2,4-pyrimidinediaminederivative A-6. Alternatively, 2-chloro-4-amino-pyrimidine A-28 can bereacted with compound A-16 to give compound A-4, which, on reaction withamine A-5, yields A-6.

A variety of pyrimidines A-26 and A-28 suitable for use as startingmaterials in Scheme (V) are commercially available from GeneralIntermediates of Canada, Inc., Edmonton, Calif., and/or Interchim,Cedex, France, or can be prepared using standard techniques. Myriadtextbook references teaching suitable synthetic methods are providedinfra.

Alternatively, 4-chloro-2-pyrimidineamines A-26 can be prepared asillustrated in Scheme (Va):

In Scheme (Va), X is as previously defined for Scheme I. In Scheme (Va),dialdehyde A-29 is reacted with guanidine to yield 2-pyrimidineamineA-30. Reaction with a peracid such as m-chloroperbenzoic acid,trifluoroperacetic acid, or urea hydrogen peroxide complex yieldsN-oxide A-31, which is then halogenated to give4-chloro-2-pyrimidineamine A-26. Corresponding 4-halo-2-pyrimidineaminescan be obtained by using suitable halogenation reagents.

In yet another exemplary implementation, the 2,4-pyrimidinediaminecompounds of the invention can be prepared from substituted orunsubstituted uridines as illustrated in Scheme (VI), below:

In Scheme (VI), ring A, ring B, R², R³, X, W, p, and q are as previouslydefined for Scheme (I) and PG represents a protecting group, asdiscussed in connection with Scheme (IIb). According to Scheme (VI),uridine A-32 has a C4 reactive center such that reaction with amine A-3or protected amine A-34 yields N4-substituted cytidine A-33 or A-35,respectively. Acid-catalyzed deprotection of N4-substituted A-33 or A-35(when “PG” represents an acid-labile protecting group) yieldsN4-substituted cytosine A-17, which can be subsequently halogenated atthe C2-position and reacted with amine A-5 to yield a2,4-pyrimidinediamine derivative A-6.

Cytidines may also be used as starting materials in an analogous manner,as illustrated in Scheme (VII), below:

In Scheme (VII), ring A, ring B, R², R³, X, W, p, and q are aspreviously defined in Scheme (I) and PG represents a protecting group asdiscussed above. Referring to Scheme (VII), cytidine A-36 has a C4reactive amine such that reaction with electrophile A-16 or A-18 yieldsN4-substituted cytidine A-33 or A-35, respectively. These cytidines A-33and A-35 are then treated as previously described for Scheme (VI) toyield a 2,4-pyrimidinediamine derivative A-6.

Although Schemes (VI) and (VII) are exemplified with ribosylnucleosides,skilled artisans will appreciate that the corresponding 2′-deoxyribo and2′,3′-dideoxyribo nucleosides, as well as nucleosides including sugarsor sugar analogs other than ribose would also work.

Numerous uridines and cytidines useful as starting materials in Schemes(VI) and (VII) are known in the art and include, by way of example andnot limitation, 5-trifluoromethyl-2′-deoxycytidine (Chem. Sources #ABCRF07669; CAS Registry 66,384-66-5); 5-bromouridine (Chem. Sources Intl2000; CAS Registry 957-75-5); 5-iodo-2′-deoxyuridine (Aldrich #1-775-6;CAS Registry 54-42-2); 5-fluorouridine (Aldrich #32,937-1; CAS Registry316-46-1); 5-iodouridine (Aldrich #85,259-7; CAS Registry 1024-99-3);5-(trifluoromethyl)uridine (Chem. Sources Int'l 2000; CAS Registry70-00-8); and 5-trifluoromethyl-2′-deoxyuridine (Chem. Sources Int'l2000; CAS Registry 70-00-8). Additional uridines and cytidines that canbe used as starting materials in Schemes (VI) and (VII) are availablefrom General Intermediates of Canada, Inc., Edmonton, Calif., and/orInterchim, Cedex, France, or can be prepared using standard techniques.Myriad textbook references teaching suitable synthetic methods areprovided infra.

Although many of the synthetic schemes discussed above do not illustratethe use of protecting groups, skilled artisans will recognize that insome instances certain substituents, such as, for example, R² and/or R⁴,may include functional groups requiring protection. The exact identityof the protecting group used will depend upon, among other things, theidentity of the functional group being protected and the reactionconditions used in the particular synthetic scheme and will be apparentto those of skill in the art. Guidance for selecting protecting groupsand their attachment and removal suitable for a particular applicationcan be found, for example, in Greene & Wuts, supra.

Prodrugs as described herein can be prepared by routine modification ofthe above-described methods. Alternatively, such prodrugs can beprepared by reacting a suitably protected 2,4-pyrimidinediamine A-6 witha suitable progroup. Conditions for carrying out such reactions and fordeprotecting the product to yield a prodrugs as described herein arewell-known.

Myriad references teaching methods useful for synthesizing pyrimidinesgenerally, as well as starting materials described in Schemes (I)-(VII),are known in the art. For specific guidance, the reader is referred toBrown, D. J., “The Pyrimidines”, in The Chemistry of HeterocyclicCompounds, Volume 16 (Weissberger, A., Ed.), 1962, IntersciencePublishers, (A Division of John Wiley & Sons), New York (“Brown I”);Brown, D. J., “The Pyrimidines”, in The Chemistry of HeterocyclicCompounds, Volume 16, Supplement I (Weissberger, A. and Taylor, E. C.,Ed.), 1970, Wiley-Interscience, (A Division of John Wiley & Sons), NewYork (Brown II″); Brown, D. J., “The Pyrimidines”, in The Chemistry ofHeterocyclic Compounds, Volume 16, Supplement II (Weissberger, A. andTaylor, E. C., Ed.), 1985, An Interscience Publication (John Wiley &Sons), New York (“Brown III”); Brown, D. J., “The Pyrimidines” in TheChemistry of Heterocyclic Compounds, Volume 52 (Weissberger, A. andTaylor, E. C., Ed.), 1994, John Wiley & Sons, Inc., New York, pp. 1-1509(Brown IV″); Kenner, G. W. and Todd, A., in Heterocyclic Compounds,Volume 6, (Elderfield, R. C., Ed.), 1957, John Wiley, New York, Chapter7 (pyrimidines); Paquette, L. A., Principles of Modern HeterocyclicChemistry, 1968, W. A. Benjamin, Inc., New York, pp. 1-401 (uracilsynthesis pp. 313, 315; pyrimidinediamine synthesis pp. 313-316; aminopyrimidinediamine synthesis pp. 315); Joule, J. A., Mills, K. and Smith,G. F., Heterocyclic Chemistry, 3^(rd) Edition, 1995, Chapman and Hall,London, UK, pp. 1-516; Vorbrüggen, H. and Ruh-Pohlenz, C., Handbook ofNucleoside Synthesis, John Wiley & Sons, New York, 2001, pp. 1-631(protection of pyrimidines by acylation pp. 90-91; silylation ofpyrimidines pp. 91-93); Joule, J. A., Mills, K. and Smith, G. F.,Heterocyclic Chemistry, 4^(th) Edition, 2000, Blackwell Science, Ltd,Oxford, UK, pp. 1-589; and Comprehensive Organic Synthesis, Volumes 1-9(Trost, B. M. and Fleming, I., Ed.), 1991, Pergamon Press, Oxford, UK.

Pharmaceutically acceptable salts also include salts formed when anacidic proton present in the parent compound is either replaced by ametal ion (e.g., an alkali metal ion, an alkaline earth metal ion or analuminum ion) or coordinates with an organic base (e.g., ethanolamine,diethanolamine, triethanolamine, N-methylglucamine, morpholine,piperidine, dimethylamine, diethylamine, triethylamine, ammonia, etc.).

The 2,4-pyrimidinediamine compounds and prodrugs thereof, as well as thesalts thereof, may also be in the form of hydrates, solvates andN-oxides, as are well-known in the art.

In another implementation, this invention provides a compound, orstereoisomer, tautomer, prodrug, solvate, or pharmaceutically acceptablesalt thereof, selected from Tables I-V.

EXAMPLES

The invention is further understood by reference to the followingexamples, which are intended to be purely exemplary of the invention.The present invention is not limited in scope by the exemplifiedimplementations, which are intended as illustrations of single aspectsof the invention only. Any methods that are functionally equivalent arewithin the scope of the invention. Various modifications of theinvention in addition to those described herein will become apparent tothose skilled in the art from the foregoing description and accompanyingfigures. Such modifications fall within the scope of the appendedclaims.

In the examples below as well as throughout the application, thefollowing abbreviations have the following meanings. If not defined, theterms have their generally accepted meanings.

aq. = aqueous br = broad DMSO = dimethylsulfoxide d = doublet dd =double of doublets ddd = doublet of doublet of doublets br = broad s =singlet t = triplet dt = doublet of triplets q = quartet m = multiplet g= gram h = hour HCl = hydrochloric acid L = Liter LC = liquidchromatography MS = mass spectrum MHz = mega hertz μL = microliter mg =milligram mL = milliliter min. = minute m/z = mass to charge ratio N =normal NMR = nuclear magnetic resonance Pd/C = palladium on carbon psi =pounds per square inch rt = room temperature IC₅₀ = The concentration ofan inhibitor that is required for 50% inhibition of an enzyme in vitroTFA = trifluoroacetic acid

A. Example 1N4-(4-cyclopropylsulfonylaminomethyl)phenyl-N2-(3,5-dimethyl)phenyl-5-fluoro-2,4-pyrimidinediamine(II-4)

4-Nitrobenzylamine HCl (1.5 g), cyclopropanesulfonyl chloride (1 g) andtriethylamine (3 mL) were dissolved in dichloromethane (20 mL). Thereaction solution was stirred at rt overnight. The reaction mixture wasdiluted with 1N HCl aq. solution (50 mL) and water (100 mL). Thesolution was extracted with ethyl acetate (2×100 mL). The organicsolution was evaporated to giveN-cyclopropylsulfonyl-4-nitrobenzylamine. ¹H NMR (DMSO-d₆): δ 0.89 (d,J=7.8 Hz, 4H), 4.33 (d, J=6.6 Hz, 2H), 7.61 (d, J=8.7 Hz, 2H), 7.83 (t,J=6.6 Hz, 1H), 8.20 (d, J=8.7 Hz, 2H).

N-Cyclopropylsulfonyl-4-nitrobenzylamine was dissolved in methanol (50mL) and to the solution was added 10% Pd—C. The reaction mixture wasreacted under hydrogen atmosphere (˜40 psi) for 1 h. The catalyst wasfiltered off over celite and washed with methanol (1 L) and water (10mL). The filtrate was evaporated to giveN-cyclopropylsulfonyl-4-aminobenzylamine. ¹H NMR (DMSO-d₆): δ 0.87 (m,4H), 2.37 (m, 1H), 3.96 (d, J=6.0 Hz, 2H), 4.99 (br, 2H), 6.49 (d, J=8.1Hz, 2H), 6.96 (d, J=8.4 Hz, 2H), 7.33 (t, J=6.0 Hz, 1H).

N-Cyclopropylsulfonyl-4-aminobenzylamine and2,6-dichloro-5-fluoropyrimidine (1.5 g) were dissolved in methanol (10mL) and water (2 mL). The reaction solution was stirred at rt overnight.The reaction solution was diluted with water (150 mL) and sonicated. Theprecipitate was filtered off, washed with water and dried to give2-chloro-N4-(4-cyclopropylsulfonylaminomethyl)phenyl-5-fluoro-4-pyrimidineamine.¹H NMR (DMSO-d₆): δ 0.89 (m, 4H), 4.16 (d, J=6.3 Hz, 2H), 7.34 (d, J=8.4Hz, 2H), 7.60 (t, 1H), 7.61 (d, J=8.1 Hz, 2H), 8.29 (d, J=3.6 Hz, 1H),9.98 (br, 1H); ¹⁹F NMR (282 MHz, DMSO-d₆): 6-192.77.

2-Chloro-N4-(4-cyclopropylsulfonylaminomethyl)phenyl-5-fluoro-4-pyrimidineamine(80 mg) and 3,5-dimethylaniline (80 mg) were suspended in isopropanol (1mL) and TFA (5 drops). The solution was heated at 100° C. overnight. Thesolution was diluted with methanol (5 mL), sonicated and the precipitatewas filtered off to giveN4-(4-cyclopropylsulfonylaminomethyl)phenyl-N2-(3,5-dimethyl)phenyl-5-fluoro-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ 0.89 (m, 4H), 2.19 (s, 6H), 2.45 (m, 1H), 4.14 (d,J=6.3 Hz, 2H), 6.60 (s, 1H), 7.18 (s, 2H), 7.28 (d, J=8.4 Hz, 2H), 7.58(t, J=6.0 Hz, 1H), 7.71 (d, J=8.4 Hz, 2H), 8.11 (d, J=4.2 Hz, 1H), 9.28(br, 1H), 9.62 (br, 1H); ¹⁹F NMR (282 MHz, DMSO-d₆): δ −163.21; LCMS:purity: 97.23%; MS (m/e): 442.78 (MH⁺).

The following compounds were made in a similar fashion to the example 1or by methods described herein or known to skilled artisans.

I-1:5-Fluoro-N4-[3-(prop-2-ynylaminosulfonyl)phenyl]-N2-(3,4,5-trimethoxyphenyl)-2,4-pyrimidinediamine

LCMS: purity: 97%; MS (m/e): 489 (MH⁺); ¹H NMR (DMSO-d6): δ 9.67 (s,1H), 9.07 (s, 1H), 8.39-8.34 (m, 1H), 8.14 (d, J=3.3 Hz, 2H), 8.10 (d,J=5.7 Hz, 1H), 7.98-7.94 (m, 2H), 7.50-7.43 (m, 2H), 7.00 (s, 2H), 3.67(dd, J=2.4 and 6.0 Hz, 2H), 3.63 (s, 6H), 3.59 (s, 3H), 3.07 (t, J=2.4Hz, 1H);

I-2:N4-(3-Aminosulfonyl-4-methylphenyl)-5-methyl-N2-[4-(prop-2-ynyloxy)phenyl]-2,4-pyrimidinediamine

LCMS: purity: 98%; MS (m/e): 425 (MH⁺); ¹H NMR (DMSO-d₆): δ 8.74 (s,1H), 8.47 (s, 1H), 8.11 (d, J=2.1 Hz, 1H), 7.94 (dd, J=2.4 and 8.4 Hz,1H), 7.85 (s, 1H), 7.52 (d, J=9.0 Hz, 2H), 7.32 (s, 2H), 7.26 (d, J=8.7Hz, 1H), 6.83 (d, J=9.0 Hz, 2H), 4.70 (d, J=2.4 Hz, 2H), 3.52 (t, J=2.1Hz, 1H), 2.59 (s, 3H), 2.09 (s, 3H).

I-3:N4-(3-Aminosulfonyl-4-methylphenyl)-N2-[4-(prop-2-ynyloxy)phenyl]-5-trifluoromethyl-2,4-pyrimidinediamine

¹H NMR (DMSO-d₆): δ 8.86 (s, 1H), 8.31 (s, 1H), 7.92-7.83 (m, 1H),7.63-7.54 (m, 1H), 7.42-7.30 (m, 6H), 6.80-9.71 (m, 2H), 4.69 (d, J=2.1Hz, 2H), 3.52 (t, J=2.1 Hz, 1H), 2.61 (s, 3H); LCMS: purity: 97%; MS(m/e): 479 (MH⁺).

I-4:N2-(3,5-Dimethyl-4-methoxyphenyl)-5-fluoro-N4-[3-(prop-2-ynylaminosulfonyl)phenyl]-2,4-pyrimidinediamine

¹H NMR (DMSO-d₆): δ 9.61 (s, 1H), 8.95 (s, 1H), 8.38-8.32 (m, 1H),8.13-8.07 (m, 2H), 7.98-7.93 (m, 1H), 7.52-7.43 (m, 2H), 7.23 (s, 2H),3.70-3.66 (m, 3H), 3.59 (s, 3H), 3.05 (t, J=2.1 Hz, 1H), 2.14 (s, 6H);LCMS: purity: 98%; MS (m/e): 457 (MH⁺).

I-5:N2-(3,5-Dimethyl-4-methoxyphenyl)-5-fluoro-N4-[4-(prop-2-ynylaminosulfonyl)phenyl]-2,4-pyrimidinediamine

¹H NMR (DMSO-d₆): δ 9.32 (s, 1H), 8.96 (s, 1H), 8.06 (d, J=3.9 Hz, 1H),7.80 (d, J=8.7 Hz, 2H), 7.59 (t, J=5.7 Hz, 1H), 7.29 (d, J=8.7 Hz, 2H),7.24 (s, 2H), 4.33 (s, 2H), 3.78-3.75 (m, 2H), 3.60 (s, 3H), 3.33 (t,J=2.1 Hz, 1H), 2.16 (s, 6H).

I-6:5-Amino-N4-(4-aminosulfonylphenyl)-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine

LCMS: ret. time: 2.86 min.; Purity: 99%; MS (m/e): 444 (MH⁺); ¹H NMR(DMSO-d6): δ 9.82 (s, 1H), 9.57 (s, 1H), 8.90 (qt, 1H, J=4.7 Hz), 7.88(d, 2H, J=8.8 Hz), 7.77 (d, 1H, J=8.5 Hz), 7.51 (s, 1H), 7.32 (s, 2H),7.32 (t, 1H, J=8.2 Hz), 7.09-7.05 (m, 2H), 6.69 (dd, 1H, J=2.0 and 8.2Hz), 4.41 (s, 2h), 2.63 (d, 3H, J=4.7 Hz).

I-7:5-Amino-N4-(3-aminosulfonylphenyl)-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine

LCMS: ret. time: 2.07 min.; Purity: 99%; MS (m/e): 444 (MH⁺); ¹H NMR(DMSO-d6): δ 9.80 (s, 1H), 9.61 (s, 1H), 8.14-8.10 (m, 1H), 7.98 (qt,1H, J=4.7 Hz), 7.91-7.89 (app s, 1H), 7.60-7.50 (m, 3H), 7.40 (s, 2H),7.20 (t, 1H, J=8.2 Hz), 7.07-7.04 (m, 2H), 6.65 (dd, 1H, J=2.3 and 8.8Hz), 4.36 (s, 2H), 2.64 (d, 3H, J=4.7 Hz).

I-8:5-Amino-N4-(3-aminosulfonylphenyl)-N2-(4-methoxyphenyl)-N2-methyl-2,4-pyrimidinediamine

LCMS: ret. time: 3.56 min.; Purity: 99%; MS (m/e): 401 (MH⁺); ¹H NMR(DMSO-d6): δ8.53 (s, 1H), 8.11 (s, 1H), 7.97 (d, 1H, J=8.5 Hz), 7.66 (s,1H), 7.41-7.23 (m, 7H), 6.99 (d, 1H, J=8.5 Hz), 3.83 (s, 3H), 3.39 (s,3H).

I-9:5-Amino-N4-(4-aminosulfonylphenyl)-N2-(4-methoxyphenyl)-N2-methyl-2,4-pyrimidinediamine

LCMS: ret. time: 3.44 min.; Purity: 99%; MS (m/e): 401 (MH⁺); ¹H NMR(DMSO-d6): δ 8.51 (s, 1H), 7.75 (s, 1H), 7.74 (d, 2H, J=8.2 Hz), 7.57(d, 2H, J=8.2 Hz), 7.30-7.21 (m, 4H), 7.03 (d, 2H, J=8.8 Hz), 3.86 (s,3H), 3.39 (s, 3H).

I-10:5-Amino-N4-(3-aminosulfonylphenyl)-N2-(3-methoxyphenyl)-N2-methyl-2,4-pyrimidinediamine

LCMS: ret. time: 3.54 min.; Purity: 99%; MS (m/e): 401 (MH⁺); ¹H NMR(DMSO-d6): δ 8.58 (s, 1H), 8.12 (s, 2H), 8.04 (dd, 1H, J=0.9 and 8.2Hz), 7.70 (d, 1H, J=0.9 Hz), 7.46-7.26 (m, 4H), 6.96-6.88 (m, 2H),6.79-6.75 (m 1H), 3.76 (s, 3H), 3.45 (s, 3H).

I-11:5-Amino-N4-(4-aminosulfonylphenyl)-N2-(3-methoxyphenyl)-N2-methyl-2,4-pyrimidinediamine

LCMS: ret. time: 3.48 min.; Purity: 99%; MS (m/e): 401 (MH⁺); ¹H NMR(DMSO-d6): δ8.47 (s, 1H), 7.73 (s, 1H), 7.72 (d, 2H, J=8.5 Hz), 7.69 (s,1H), 7.52 (d, 1H, J=8.5 Hz), 7.30-7.25 (m, 1H), 7.15 (s, 2H), 6.88-6.86(m, 2H), 6.76 (app d, 1H, J=8.2 Hz), 3.72 (s, 3H), 3.37 (s, 3H).

I-12:N4-(3-Aminosulfonylphenyl)-N2-[4-(2-pyridinyl)methyleneoxyphenyl]-5-trifluoromethyl-2,4-pyrimidinediamine

LCMS (m/z): 517 (MH⁺); ¹H NMR (DMSO d₆, 300 MHz): δ 9.52 (s, 1H), 8.92(s, 1H), 8.53 (d, 1H, J=4.2 Hz), 8.31 (s, 1H), 7.78 (t, 3H, J=7.8 Hz),7.58 (d, 1H, J=6.6 Hz), 7.46 (m, 2H), 7.33 (m, 5H), 6.80 (br s, 2H),5.06 (s, 2H).

I-13:N4-[4-N—(Cyclopropyl)aminosulfonylphenyl]-N2-[4-(3-pyridinyl)methyleneoxyphenyl]-5-trifluoromethyl-2,4-pyrimidinediamine

LCMS (m/z): 557 (MH⁺); ¹H NMR (DMSO d₆, 300 MHz): δ 9.65 (s, 1H), 8.63(s, 1H), 8.52 (s, 1H), 8.38 (s, 1H), 7.93 (s, 1H), 7.83 (d, 1H, J=8.1Hz), 7.74 (s, 2H), 7.41 (m, 3H), 6.84 (s, 2H), 6.73 (d, 1H, J=7.8 Hz),6.52 (d, 1H, J=8.1 Hz), 5.07 (s, 2H), 2.10 (m, 1H), 0.46 (m, 2H), 0.41(m, 2H).

I-14:N4-[(3-(1,1-Dimethylamino)sulfonyl)phenyl]-5-methyl-N2-[4-(4-methyl-1-piperazinyl)phenyl]-2,4-pyrimidinediamine

LCMS: Purity: 98%; MS (m/e): 510 (MH⁺); ¹H NMR (DMSO-d6): δ8.67 (s, 1H),8.48 (s, 1H), 8.10 (app s, 2H), 7.86 (s, 1H), 7.53 (s, 1H), 7.46 (m,3H), 6.79 (d, 2H, J=9.1 Hz), 3.00-2.99 (m, 4H), 2.44-2.43 9m, 4H), 2.20(s, 3H), 2.09 (s, 3H), 1.10 (s, 9H).

I-15:5-Chloro-N4-[3-(N-tert-butylsulfonyl)phenyl]-N2-[3,4,5-trimethoxyphenyl]-2,4-pyrimidinediamine

LCMS: purity: 99%; MS (m/e): 523 (MH⁺)

I-16:5-Chloro-N4-[3-(N-tert-butylsulfonyl)phenyl]-N2-[3,4-trimethyl-4-methoxyphenyl]-2,4-pyrimidinediamine

LCMS: purity: 99%; MS (m/e): 491 (MH⁺)

I-17:5-Chloro-N4-[3-(N-tert-butylsulfonyl)phenyl]-N2-[4-(N-methylpiperidin-4-yl)phenyl]-2,4-pyrimidinediamine

LCMS: purity: 99%; MS (m/e): 531 (MH⁺); ¹H NMR (DMSO-d6): δ8.11 (d, 1H,J=1.8 Hz), 7.41 (m, 3H), 7.24 (m, 1H), 6.93 (d, 1H, J=8.4 Hz), 6.71 (d,2H, J=9 Hz), 3.10 (s, 8H), 2.97 (s, 3H), 2.60 (s, 6H), 1.42 (s, 9H);

I-18:5-Bromo-N4-[3-(N-tert-butylsulfonyl)phenyl]-N2-[4-(4-methylpiperazine)-phenyl]-2,4-pyrimidinediamine

LCMS: purity: 99%; MS (m/e): 575 (MH⁺); ¹H NMR (DMSO-d6): δ8.11 (s, 1H),7.99 (m, 2H), 7.59 (s, 1H), 7.54 (d, 1H, J=7.6 Hz), 7.41 (m, 2H), 6.88(d, 2H, J=9.3 Hz), 6.17 (d, 1H, J=3.4 Hz), 3.15 (m, 4H), 2.84 (m, 4H),1.10 (s, 9H);

I-19:N4-[3-(N-tert-butylsulfonyl)phenyl]-N2-[4-(4-methylpiperazine)-phenyl]-2,4-pyrimidinediamine

LCMS: purity: 99%; MS (m/e): 496 (MH⁺)

I-20:5-Methyl-N4-[3-(N-tert-butylsulfonyl)phenyl]-N2-[3,5-dimethyl-4-(2-(1-morpholino)ethoxyphenyl]-2,4-pyrimidinediamine

LCMS: purity: 99%; MS (m/e): 569 (MH⁺); ¹H NMR (DMSO-d6): δ8.11 (s, 1H),7.41 (m, 3H), 8.04 (d, 1H, J=6.1 Hz), 7.93 (s, 2H), 7.54 (m, 3H), 7.16(s, 2H), 3.99 (m, 2H), 3.53 (m, 3H), 2.12 (m, 9H), 1.12 (m, 11H);

I-21:5-Chloro-N4-[3-(N-tert-butylsulfonyl)phenyl]-N2-[3,5-dimethyl-4-(2-(1-morpholino)ethoxyphenyl]-2,4-pyrimidinediamine

LCMS: purity: 99%; MS (m/e): 590 (MH⁺)

I-22:5-Chloro-N4-[(3-(1,1-dimethylethylamino)sulfonyl)phenyl]-N2-[3-methyl-4-[(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]phenyl]-2,4-pyrimidinediamine

LCMS: Purity: 99%; MS (m/e): 556 (MH⁺); ¹H NMR (DMSO-d6): δ 9.05 (s,1H), 8.99 (s, 1H), 8.03-8.01 (s, 2H), 7.53-7.42 (m, 3H), 7.22 (s, 1H),7.19 (d, 1H, J=8.8 Hz), 6.62 (d, 1H, J=8.5 Hz), 3.83 (s, 1H), 3.28 (s,1H), 3.17-3.10 (m, 2H), 2.66 (dd, 1H, J=9.0 and 17.7 Hz), 2.24 (s, 3H),2.06 (s, 3H), 1.69 (dd, 2H, J=9.0 and 17.7 Hz), 1.09 (s, 9H).

II-1:N4-(4-cyclopropylsulfonylaminomethyl)phenyl-5-fluoro-N2-(3,4,5-trimethoxy)phenyl-2,4-pyrimidinediamine

LCMS: purity: 97.84%; MS (m/e): 504.67 (MH+); ¹H NMR (DMSO-d₆): δ 0.90(m, 4H), 2.44 (m, 1H), 3.58 (s, 3H), 3.62 (s, 6H), 4.14 (d, J=5.7 Hz,2H), 7.02 (s, 2H), 7.26 (d, J=8.1 Hz, 2H), 7.58 (t, J=6.0 Hz, 1H), 7.74(d, J=7.8 Hz, 2H), 8.07 (d, J=2.7 Hz, 1H), 9.02 (s, 1H), 9.30 (s, 1H);¹⁹F NMR (282 MHz, DMSO-d₆): −164.01.

II-2:N4-(4-cyclopropylsulfonylaminomethyl)phenyl-N2-(3,4-difluoro)phenyl-5-fluoro-2,4-pyrimidinediamine

LCMS: purity: 96.48%; MS (m/e): 450.64 (MH⁺); ¹H NMR (DMSO-d₆): δ 0.89(m, 4H), 2.44 (m, 1H), 4.16 (d, J=5.7 Hz, 2H), 7.27 (m, 2H), 7.31 (d,J=8.1 Hz, 2H), 7.59 (t, J=6.3 Hz, 1H), 7.68 (d, J=8.1 Hz, 2H), 7.84(ddd, 1H), 8.12 (d, J=3.9 Hz, 1H), 9.47 (s, 1H), 9.51 (s, 1H); ¹⁹F NMR(282 MHz, DMSO-d₆): −162.93, −148.04, −138.00.

II-3:N2-(3-chloro-4-methoxy)phenyl-N4-(4-cyclopropylsulfonylaminomethyl)phenyl-5-fluoro-2,4-pyrimidinediamine

LCMS: purity: 94.85%; MS (m/e): 477.99 (MH⁺); ¹H NMR (DMSO-d₆): δ 0.89(m, 4H), 2.43 (m, 1H), 3.78 (s, 3H), 4.15 (d, J=6.0 Hz, 2H), 7.00 (d,J=9.3 Hz, 1H), 7.29 (d, J=8.4 Hz, 2H), 7.45 (dd, J=2.1, 9.0 Hz, 1H),7.59 (t, J=6.3 Hz, 1H), 7.71 (d, J=8.1 Hz, 2H), 7.82 (d, J=1.8 Hz, 1H),8.07 (d, J=3.0 Hz, 1H), 9.15 (s, 1H), 9.33 (s, 1H); ¹⁹F NMR (282 MHz,DMSO-d₆): δ −164.14;

II-5:N2-(3-chloro-4-cyano)phenyl-N4-(4-cyclopropylsulfonylaminomethyl)phenyl-5-fluoro-2,4-pyrimidinediamine

¹H NMR (DMSO-d₆): δ 0.90 (m, 4H), 4.17 (d, J=6.6 Hz, 2H), 7.34 (d, J=8.4Hz, 2H), 7.60 (m, 2H), 7.65 (d, J=7.8 Hz, 2H), 7.72 (d, J=8.4 Hz, 1H),8.16 (s, 1H), 8.19 (d, J=3.9 Hz, 1H), 9.56 (s, 1H), 9.97 (s, 1H); ¹⁹FNMR (282 MHz, DMSO-d₆): −161.00; LCMS: purity: 81.37%; MS (m/e): 473.03(MH+).

II-6:N4-(4-cyclopropylsulfonylaminomethyl)phenyl-N2-[4-(4-ethylpiperazino)-3-methyl]phenyl-5-fluoro-2,4-pyrimidinediamine

LCMS: purity: 99.65%; MS (m/e): 540.20 (MH+); ¹H NMR (DMSO-d₆): δ 0.89(m, 4H), 1.02 (t, J=6.9 Hz, 3H), 2.17 (s, 3H), 2.40 (m, 4H), 2.78 (m,4H), 4.14 (d, J=6.3 Hz, 2H), 6.89 (d, J=8.4 Hz, 1H), 7.26 (d, J=8.4 Hz,2H), 7.34 (d, J=8.1 Hz, 1H), 7.43 (s, 1H), 7.57 (t, J=6.3 Hz, 1H), 7.74(d, J=8.1 Hz, 2H), 8.03 (d, J=3.9 Hz, 1H), 8.94 (br, 1H), 9.25 (br, 1H);¹⁹F NMR (282 MHz, DMSO-d₆): δ −164.80;

II-7:N4-(4-cyclopropylsulfonylaminomethyl)phenyl-N2-(3,5-dimethyl)phenyl-5-methyl-2,4-pyrimidinediamine

LCMS: purity: 96.13%; MS (m/e): 438.66 (MH+); ¹H NMR (DMSO-d₆): δ 0.90(m, 4H), 2.10 (s, 3H), 2.15 (s, 6H), 2.43 (m, 1H), 4.14 (d, J=6.6 Hz,2H), 6.50 (s, 1H), 7.21 (s, 2H), 7.27 (d, J=8.4 Hz, 2H), 7.58 (t, J=6.0Hz, 1H), 7.65 (d, J=8.1 Hz, 2H), 7.84 (s, 1H), 8.39 (br, 1H), 8.93 (br,1H).

II-8:N4-(4-cyclopropylsulfonylaminomethyl)phenyl-N2-[4-(4-ethylpiperazino)-3-methyl]phenyl-5-methyl-2,4-pyrimidinediamine

LCMS: purity: 85.23%; MS (m/e): 536.44 (MH⁺); ¹H NMR (DMSO-d₆): δ 0.89(m, 4H), 1.02 (t, J=7.2 Hz, 3H), 2.08 (s, 3H), 2.14 (s, 3H), 2.36 (q,J=7.2 Hz, 2H), 2.77 (m, 4H), 4.14 (d, J=6.0 Hz, 2H), 6.85 (d, J=8.7 Hz,1H), 7.26 (d, J=8.4 Hz, 2H), 7.36 (d, J=9.0 Hz, 1H), 7.42 (s, 1H), 7.58(t, J=6.6 Hz, 1H), 7.68 (d, J=8.1 Hz, 2H), 7.82 (s, 1H), 8.18 (br, 1H),8.71 (br, 1H).

II-9:N4-(4-cyclopropylsulfonylaminomethyl)phenyl-5-methyl-N2-(3,4,5-trimethoxy)phenyl-2,4-pyrimidinediamine

LCMS: purity: 99.29%; MS (m/e): 500.15 (MH+); ¹H NMR (DMSO-d₆): δ 0.91(m, 4H), 2.09 (s, 3H), 3.57 (s, 9H), 4.14 (d, J=6.3 Hz, 2H), 7.04 (s,2H), 7.24 (d, J=8.4 Hz, 2H), 7.55 (t, J=6.3 Hz, 1H), 7.67 (d, J=8.4 Hz,2H), 7.86 (s, 1H), 8.21 (s, 1H), 8.76 (s, 1H).

II-10:N2-(3-chloro-4-methoxy)phenyl-N4-(4-cyclopropylsulfonylaminomethyl)phenyl-5-methyl-2,4-pyrimidinediamine

LCMS: purity: 99.46%; MS (m/e): 474.07 (MH+); ¹H NMR (DMSO-d₆): δ 0.88(m, 4H), 2.14 (s, 3H), 3.82 (s, 3H), 4.17 (d, J=6.9 Hz, 2H), 7.03 (d,J=9.6 Hz, 1H), 7.32 (d, J=8.7 Hz, 3H), 7.53 (d, J=8.1 Hz, 2H), 7.62 (m,2H), 7.81 (s, 1H).

II-11:N4-(3-cyclopropylsulfonylaminomethyl)phenyl-N2-(3,5-dimethyl)phenyl-5-methyl-2,4-pyrimidinediamine

LCMS: purity: 99.63%; MS (m/e): 438.49 (MH⁺); ¹H NMR (DMSO-d₆): δ 0.85(m, 4H), 2.10 (s, 3H), 2.12 (s, 6H), 4.15 (d, J=6.3 Hz, 2H), 6.46 (s,1H), 7.02 (d, J=7.8 Hz, 1H), 7.24 (s, 2H), 7.26 (m, 1H), 7.59 (m, 2H),7.71 (d, J=8.1 Hz, 1H), 7.86 (s, 1H), 8.28 (s, 1H), 8.73 (s, 1H).

II-12:N4-(3-cyclopropylsulfonylaminomethyl)phenyl-N2-[4-(4-ethylpiperazino)-3-methyl]phenyl-5-methyl-2,4-pyrimidinediamine

LCMS: purity: 99.52%; MS (m/e): 536.39 (MH+); ¹H NMR (DMSO-d₆): δ 0.86(m, 4H), 1.02 (t, J=7.2 Hz, 3H), 2.09 (s, 3H), 2.12 (s, 3H), 2.42 (q,2H), 2.76 (m, 4H), 4.16 (d, J=6.0 Hz, 2H), 6.84 (d, J=9.0 Hz, 1H), 7.02(d, J=7.8 Hz, 1H), 7.26 (t, J=7.8 Hz, 1H), 7.38 (m, 2H), 7.59 (t, J=6.0Hz, 1H), 7.65 (m, 2H), 7.83 (s, 1H), 8.24 (s, 1H), 8.66 (s, 1H).

II-13:N4-(3-cyclopropylsulfonylaminomethyl)phenyl-5-methyl-N2-(3,4,5-trimethoxy)phenyl-2,4-pyrimidinediamine

LCMS: purity: 94.43%; MS (m/e): 500.21 (MH+); ¹H NMR (DMSO-d₆): δ 0.88(m, 4H), 2.10 (s, 3H), 3.56 (s, 6H), 3.57 (s, 3H), 4.13 (d, J=6.0 Hz,2H), 7.00 (m, 1H), 7.02 (s, 2H), 7.23 (t, J=7.8 Hz, 1H), 7.56 (t, J=5.7Hz, 1H), 7.67 (m, 2H), 7.87 (s, 1H), 8.30 (s, 1H), 8.73 (s, 1H).

II-14:N2-(3-chloro-4-methoxy)phenyl-N4-(3-cyclopropylsulfonylaminomethyl)phenyl-5-methyl-2,4-pyrimidinediamine

LCMS: purity: 99.53%; MS (m/e): 474.11 (MH⁺); ¹H NMR (DMSO-d₆): δ 0.88(m, 4H), 2.10 (s, 3H), 3.77 (s, 3H), 4.16 (d, J=6.0 Hz, 2H), 6.96 (d,J=8.7 Hz, 1H), 7.04 (d, J=7.5 Hz, 1H), 7.29 (t, J=7.8 Hz, 1H), 7.46 (dd,J=2.4, 9.3 Hz, 1H), 7.61 (m, 3H), 7.78 (d, J=1.8 Hz, 1H), 7.86 (s, 1H),8.42 (s, 1H), 8.96 (s, 1H).

II-15:N2-(4-aminocarbonyl)phenyl-N4-(4-cyclopropylsulfonylaminomethyl)phenyl-5-fluoro-2,4-pyrimidinediamine

LCMS: purity: 93.27%; MS (m/e): 457.17 (MH+); ¹H NMR (DMSO-d₆): δ 0.89(m, 4H), 4.17 (d, J=6.0 Hz, 2H), 7.11 (br, 1H), 7.31 (d, J=8.7 Hz, 2H),7.60 (t, J=6.3 Hz, 1H), 7.71 (m, 7H), 8.12 (d, J=3.6 Hz, 1H), 9.40 (s,1H), 9.46 (s, 1H); ¹⁹F NMR (282 MHz, DMSO-d₆): δ −162.90.

II-16:N2-(3-aminocarbonyl)phenyl-N4-(4-cyclopropylsulfonylaminomethyl)phenyl-5-fluoro-2,4-pyrimidinediamine

LCMS: purity: 94.73%; MS (m/e): 457.06 (MH+); ¹H NMR (DMSO-d₆): δ 0.88(m, 4H), 2.42 (m, 1H), 4.14 (d, J=6.0 Hz, 2H), 7.24 (m, 2H), 7.26 (d,J=8.4 Hz, 2H), 7.35 (d, J=8.4 Hz, 1H), 7.57 (t, J=6.0 Hz, 1H), 7.76 (d,J=8.4 Hz, 2H), 7.82 (m, 2H), 8.00 (s, 1H), 8.08 (d, J=3.6 Hz, 1H), 9.28(s, 1H), 9.32 (s, 1H); ¹⁹F NMR (282 MHz, DMSO-d₆): δ −163.62.

II-17:N2-(4-aminocarbonyl)phenyl-N4-(3-chloro-4-cyclopropylsulfonylaminomethyl)phenyl-5-methyl-2,4-pyrimidinediamine

LCMS: purity: 87.50%; MS (m/e): 487.12 (MH+); ¹H NMR (DMSO-d₆): δ 0.90(m, 4H), 2.14 (s, 3H), 4.28 (d, J=6.0 Hz, 2H), 7.08 (br, 1H), 7.39 (d,J=9.0 Hz, 1H), 7.65 (t, J=5.4 Hz, 1H), 7.70 (m, 6H), 7.91 (s, 1H), 7.95(s, 1H), 8.55 (s, 1H), 9.13 (s, 1H).

II-18:N2-(3-aminocarbonyl)phenyl-N4-(3-chloro-4-cyclopropylsulfonylaminomethyl)phenyl-5-methyl-2,4-pyrimidinediamine

LCMS: purity: 86.27%; MS (m/e): 487.14 (MH+); ¹H NMR (DMSO-d₆): δ 0.90(m, 4H), 2.12 (s, 3H), 2.55 (m, 1H), 4.24 (d, J=5.7 Hz, 2H), 7.20-7.35(m, 4H), 7.64 (t, J=6.0 Hz, 1H), 7.82 (m, 3H), 7.91 (s, 2H), 8.00 (s,1H), 8.49 (s, 1H), 8.96 (s, 1H).

II-19:N2-(4-aminocarbonyl)phenyl-N4-[4-(N-cyclopropylsulfonyl-N-methyl)aminomethyl]phenyl-5-methyl-2,4-pyrimidinediamine

LCMS: purity: 87.13%; MS (m/e): 467.22 (MH+); ¹H NMR (DMSO-d₆): δ 1.00(d, J=6.9 Hz, 4H), 2.12 (s, 3H), 2.65 (m, 1H), 2.71 (s, 3H), 4.29 (s,2H), 7.07 (br, 1H), 7.30 (d, J=7.2 Hz, 2H), 7.65-7.74 (m, 7H), 7.91 (s,1H), 8.37 (s, 1H), 9.25 (s, 1H).

II-20:N2-(3-aminocarbonyl)phenyl-N4-[4-(N-cyclopropylsulfonyl-N-methyl)aminomethyl]phenyl-5-methyl-2,4-pyrimidinediamine

LCMS: purity: 83.47%; MS (m/e): 467.15 (MH⁺); ¹H NMR (DMSO-d₆): δ 0.99(d, J=6.9 Hz, 4H), 2.11 (s, 3H), 2.65 (m, 1H), 2.69 (s, 3H), 4.25 (s,2H), 7.16-7.32 (m, 5H), 7.74 (d, J=8.7 Hz, 2H), 7.75 (br, 1H), 7.90 (m,2H), 7.97 (s, 1H), 8.30 (s, 1H), 9.07 (s, 1H).

II-21:N2-(4-aminocarbonyl)phenyl-N4-[3-(N-cyclopropylsulfonyl-N-methyl)aminomethyl]phenyl-5-methyl-2,4-pyrimidinediamine

LCMS: purity: 96.03%; MS (m/e): 467.22 (MH+); ¹H NMR (DMSO-d₆): δ 0.95(m, 4H), 2.15 (s, 3H), 2.64 (s, 3H), 4.26 (s, 2H), 7.20 (m, 2H), 7.40(t, J=7.5 Hz, 1H), 7.47-7.50 (m, 3H), 7.58 (d, J=8.1 Hz, 1H), 7.69 (d,J=8.4 Hz, 2H), 7.81 (s, 1H), 7.90 (s, 1H), 9.47 (br, 1H), 10.02 (br,1H).

II-22:N2-(3-aminocarbonyl)phenyl-N4-[3-(N-cyclopropylsulfonyl-N-methyl)aminomethyl]phenyl-5-methyl-2,4-pyrimidinediamine

LCMS: purity: 98.80%; MS (m/e): 467.23 (MH⁺); ¹H NMR (DMSO-d₆): δ 1.00(d, J=6.3 Hz, 4H), 2.12 (s, 3H), 2.69 (s, 4H), 4.26 (s, 2H), 6.99 (d,J=8.1 Hz, 1H), 7.18-7.34 (m, 4H), 7.63 (s, 1H), 7.77 (s, 1H), 7.81-7.87(m, 2H), 7.89 (s, 1H), 7.97 (s, 1H), 8.34 (s, 1H), 8.99 (s, 1H).

II-23:N2-(4-aminocarbonyl)phenyl-N4-(3-cyclopropylsulfonylaminomethyl)phenyl-5-methyl-2,4-pyrimidinediamine

LCMS: purity: 98.72%; MS (m/e): 453.44 (MH+); ¹H NMR (DMSO-d₆): δ 0.85(m, 4H), 2.16 (s, 3H), 4.18 (d, J=6.0 Hz, 2H), 7.23 (m, 2H), 7.39 (t,J=7.5 Hz, 1H), 7.50 (m, 2H), 7.52 (d, J=9.3 Hz, 2H), 7.64 (t, J=6.0 Hz,1H), 7.70 (d, J=8.7 Hz, 2H), 7.81 (s, 1H), 7.90 (s, 1H), 9.39 (br, 1H),9.94 (br, 1H).

II-24:N2-(3-aminocarbonyl)phenyl-N4-(3-cyclopropylsulfonylaminomethyl)phenyl-5-methyl-2,4-pyrimidinediamine

LCMS: purity: 97.92%; MS (m/e): 453.21 (MH⁺); ¹H NMR (DMSO-d₆): δ 0.88(m, 4H), 2.12 (s, 3H), 2.45 (m, 1H), 4.16 (d, J=6.3 Hz, 2H), 7.02 (d,J=7.5 Hz, 1H), 7.18-7.33 (m, 4H), 7.59 (t, J=6.3 Hz, 1H), 7.68-7.76 (m,3H), 7.89 (s, 1H), 7.92 (m, 1H), 7.96 (s, 1H), 8.30 (s, 1H), 9.00 (s,1H).

II-25:N2-(4-cyano)phenyl-N4-(3-cyclopropylsulfonylaminomethyl)phenyl-5-methyl-2,4-pyrimidinediamine

LCMS: purity: 97.67%; MS (m/e): 435.17 (MH+); ¹H NMR (DMSO-d₆): δ 0.86(m, 4H), 2.17 (s, 3H), 2.44 (m, 1H), 4.19 (d, J=6.0 Hz, 2H), 7.24 (d,J=6.9 Hz, 1H), 7.42 (t, J=7.8 Hz, 1H), 7.46 (m, 2H), 7.58-7.68 (m, 5H),7.95 (s, 1H), 9.51 (br, 1H), 10.30 (br, 1H).

II-26:N2-(3-cyano)phenyl-N4-(3-cyclopropylsulfonylaminomethyl)phenyl-5-methyl-2,4-pyrimidinediamine

LCMS: purity: 99.44%; MS (m/e): 435.22 (MH+); ¹H NMR (DMSO-d₆): δ 0.84(m, 4H), 2.17 (s, 3H), 2.43 (m, 1H), 4.17 (d, J=6.0 Hz, 2H), 7.22 (d,J=8.1 Hz, 1H), 7.40-7.51 (m, 5H), 7.64 (m, 2H), 7.89 (s, 1H), 7.94 (s,1H), 9.76 (br, 1H), 10.51 (br, 1H).

II-27:N2-(4-cyano)phenyl-N4-[4-(N-cyclopropylsulfonyl-N-methyl)aminomethyl]phenyl-5-methyl-2,4-pyrimidinediamine

LCMS: purity: 99.60%; MS (m/e): 449.24 (MH+); ¹H NMR (DMSO-d₆): δ 1.01(d, J=6.3 Hz, 4H), 2.16 (s, 3H), 2.68 (m, 1H), 2.73 (s, 3H), 4.33 (s,2H), 7.38 (d, J=7.8 Hz, 2H), 7.56 (d, J=8.1 Hz, 2H), 7.59 (d, J=8.1 Hz,2H), 7.70 (d, J=8.7 Hz, 2H), 7.94 (s, 1H), 9.24 (br, 1H), 10.09 (br,1H).

II-28:N2-(3-cyano)phenyl-N4-[4-(N-cyclopropylsulfonyl-N-methyl)aminomethyl]phenyl-5-methyl-2,4-pyrimidinediamine

LCMS: purity: 98.87%; MS (m/e): 449.23 (MH+); ¹H NMR (DMSO-d₆): δ 1.00(d, J=6.6 Hz, 4H), 2.12 (s, 3H), 2.64 (m, 1H), 2.70 (s, 3H), 4.27 (s,2H), 7.23 (d, J=7.6.6 Hz, 1H), 7.31 (d, J=8.1 Hz, 2H), 7.34 (m, 1H),7.64 (d, J=8.4 Hz, 2H), 7.82 (d, J=8.4 Hz, 1H), 7.93 (s, 1H), 8.19 (s,1H), 8.42 (s, 1H), 9.36 (s, 1H).

II-29:N2-(4-cyano)phenyl-N4-(4-cyclopropylsulfonylaminomethyl)phenyl-5-fluoro-2,4-pyrimidinediamine

LCMS: purity: 91.78%; MS (m/e): 439.13 (MH+); ¹H NMR (DMSO-d₆): δ 0.89(m, 4H), 4.18 (d, J=6.0 Hz, 2H), 7.34 (d, J=8.1 Hz, 2H), 7.62 (d, J=9.0Hz, 2H), 7.62 (t, 1H), 7.68 (d, J=8.4 Hz, 2H), 7.86 (d, J=8.7 Hz, 2H),8.16 (d, J=3.6 Hz, 1H), 9.50 (s, 1H), 9.77 (s, 1H); ¹⁹F NMR (282 MHz,DMSO-d₆): δ −161.90.

II-30:N2-(3-cyano)phenyl-N4-(4-cyclopropylsulfonylaminomethyl)phenyl-5-fluoro-2,4-pyrimidinediamine

LCMS: purity: 96.01%; MS (m/e): 439.13 (MH+); ¹H NMR (DMSO-d₆): δ 0.90(m, 4H), 2.42 (m, 1H), 4.16 (d, J=6.3 Hz, 2H), 7.29 (d, J=9.0 Hz, 1H),7.32 (d, J=8.7 Hz, 2H), 7.39 (t, J=7.8 Hz, 1H), 7.56 (t, J=6.3 Hz, 1H),7.68 (d, J=7.8 Hz, 2H), 7.84 (d, J=6.9 Hz, 1H), 8.14 (d, J=3.3 Hz, 1H),8.18 (s, 1H), 9.46 (s, 1H), 9.57 (s, 1H); ¹⁹F NMR (282 MHz, DMSO-d₆): δ−162.71.

II-31:N2-(4-aminocarbonyl)phenyl-N4-(4-cyclopropylsulfonylaminomethyl)phenyl-5-methyl-2,4-pyrimidinediamine

LCMS: purity: 98.84%; MS (m/e): 452.89 (MH+); ¹H NMR (DMSO-d₆): δ 0.88(m, 4H), 2.17 (s, 3H), 4.24 (d, J=6.3 Hz, 2H), 7.30 (br, 1H), 7.40 (d,J=8.1 Hz, 2H), 7.49 (d, J=8.4 Hz, 2H), 7.53 (d, J=8.4 Hz, 2H), 7.70 (t,J=6.3 Hz, 1H), 7.73 (d, J=8.4 Hz, 2H), 7.80 (s, 1H), 7.92 (s, 1H), 9.74(s, 1H), 10.47 (s, 1H).

II-32:N2-(3-aminocarbonyl)phenyl-N4-(4-cyclopropylsulfonylaminomethyl)phenyl-5-methyl-2,4-pyrimidinediamine

LCMS: purity: 98.82%; MS (m/e): 452.84 (MH+); ¹H NMR (DMSO-d₆): δ 0.89(m, 4H), 2.10 (s, 3H), 2.45 (m, 1H), 4.15 (d, J=6.0 Hz, 2H), 7.19-7.32(m, 5H), 7.57 (t, J=6.3 Hz, 1H), 7.70 (d, J=8.1 Hz, 2H), 7.76 (s, 1H),7.87 (s, 1H), 7.91 (d, J=7.8 Hz, 1H), 7.96 (s, 1H), 8.24 (s, 1H), 9.06(s, 1H).

II-33:N2-(4-cyano)phenyl-N4-(4-cyclopropylsulfonylaminomethyl)phenyl-5-methyl-2,4-pyrimidinediamine

LCMS: purity: 95.37%; MS (m/e): 434.97 (MH+); ¹H NMR (DMSO-d₆): δ 0.90(m, 4H), 2.12 (s, 3H), 4.20 (d, J=6.3 Hz, 2H), 7.34 (d, J=8.4 Hz, 2H),7.56 (d, J=9.3 Hz, 2H), 7.58 (m, 1H), 7.60 (d, J=9.0 Hz, 2H), 7.85 (d,J=8.7 Hz, 2H), 7.93 (s, 1H), 8.44 (s, 1H), 9.56 (s, 1H).

II-34:N2-(3-cyano)phenyl-N4-(4-cyclopropylsulfonylaminomethyl)phenyl-5-methyl-2,4-pyrimidinediamine

LCMS: purity: 99.04%; MS (m/e): 435.16 (MH+); ¹H NMR (DMSO-d₆): δ 0.90(m, 4H), 2.11 (s, 3H), 2.44 (m, 1H), 4.17 (d, J=6.0 Hz, 2H), 7.23 (d,J=6.6 Hz, 1H), 7.32 (d, J=8.4 Hz, 2H), 7.35 (t, J=7.5 Hz, 1H), 7.53 (t,J=6.3 Hz, 1H), 7.59 (d, J=8.1 Hz, 2H), 7.85 (d, J=9.3 Hz, 1H), 7.91 (s,1H), 8.16 (s, 1H), 8.39 (s, 1H), 9.36 (s, 1H).

II-35:5-chloro-N2-(3-chloro-4-methoxy)phenyl-N4-(4-cyclopropylsulfonylaminomethyl)phenyl-2,4-pyrimidinediamine

LCMS: purity: 93.08%; MS (m/e): 494.02 (MH+); ¹H NMR (DMSO-d₆): δ 0.90(m, 4H), 3.77 (s, 3H), 4.16 (d, J=6.6 Hz, 2H), 6.95 (d, J=9.0 Hz, 1H),7.31 (d, J=8.1 Hz, 2H), 7.44 (dd, J=2.4, 8.7 Hz, 1H), 7.58 (d, J=7.8 Hz,2H), 7.61 (t, J=6.6 Hz, 1H), 7.70 (s, 1H), 8.10 (s, 1H), 8.81 (s, 1H),9.26 (s, 1H).

II-36:5-chloro-N4-(4-cyclopropylsulfonylaminomethyl)phenyl-N2-(3,5-dimethyl)phenyl-2,4-pyrimidinediamine

LCMS: purity: 91.95%; MS (m/e): 458.10 (MH+); ¹H NMR (DMSO-d₆): δ 0.90(m, 4H), 2.13 (s, 6H), 2.43 (m, 1H), 4.15 (d, J=6.3 Hz, 2H), 6.51 (s,1H), 7.18 (s, 2H), 7.29 (d, J=8.4 Hz, 2H), 7.60 (t, J=6.0 Hz, 1H), 7.61(d, J=8.1 Hz, 2H), 8.10 (s, 1H), 8.76 (s, 1H), 9.15 (s, 1H).

II-37:N2-(4-aminocarbonyl)phenyl-5-chloro-N4-(4-cyclopropylsulfonylaminomethyl)phenyl-2,4-pyrimidinediamine

LCMS: purity: 88.88%; MS (m/e): 472.99 (MH+); ¹H NMR (DMSO-d₆): δ 0.90(m, 4H), 4.20 (d, J=6.0 Hz, 2H), 7.13 (br, 1H), 7.34 (d, J=8.7 Hz, 2H),7.62 (d, J=8.4 Hz, 3H), 7.67 (s, 5H), 8.16 (s, 1H), 8.89 (s, 1H), 9.56(s, 1H).

II-38:N4-(3-chloro-4-cyclopropylsulfonylaminomethyl)phenyl-N2-(3,5-dimethyl)phenyl-5-methyl-2,4-pyrimidinediamine

LCMS: purity: 99.50%; MS (m/e): 472.20 (MH+); ¹H NMR (DMSO-d₆): δ 0.86(m, 4H), 2.10 (s, 3H), 2.13 (s, 6H), 4.25 (d, J=6.0 Hz, 2H), 6.47 (s,1H), 7.23 (s, 2H), 7.32 (d, J=8.7 Hz, 1H), 7.64 (t, J=6.0 Hz, 1H), 7.72(dd, J=2.7, 8.1 Hz, 1H), 7.85 (s, 1H), 7.89 (s, 1H), 8.47 (s, 1H), 8.68(s, 1H).

II-39:N4-[4-(N-cyclopropylsulfonyl-N-methyl)aminomethyl]phenyl-N2-(3,5-dimethyl)phenyl-5-methyl-2,4-pyrimidinediamine

LCMS: purity: 99.53%; MS (m/e): 452.62 (MH+); ¹H NMR (DMSO-d₆): δ 0.98(m, 4H), 2.10 (s, 3H), 2.13 (s, 6H), 4.24 (s, 2H), 6.46 (s, 1H), 7.24(s, 2H), 7.26 (d, J=7.8 Hz, 2H), 7.71 (d, J=8.1 Hz, 2H), 7.86 (s, 1H),8.25 (s, 1H), 8.81 (s, 1H).

II-40:N4-[3-(N-cyclopropylsulfonyl-N-methyl)aminomethyl]phenyl-N2-(3,5-dimethyl)phenyl-5-methyl-2,4-pyrimidinediamine

LCMS: purity: 97.67%; MS (m/e): 452.71 (MH+); ¹H NMR (DMSO-d₆): δ 0.98(m, 4H), 2.10 (s, 3H), 2.12 (s, 6H), 4.25 (s, 2H), 6.46 (s, 1H), 7.00(d, J=7.8 Hz, 1H), 7.23 (s, 2H), 7.29 (t, J=7.8 Hz, 1H), 7.55 (s, 1H),7.79 (d, J=8.7 Hz, 1H), 7.86 (s, 1H), 8.35 (s, 1H), 8.74 (s, 1H).

II-41:N4-(4-cyclopropylsulfonylaminomethyl)phenyl-N2-(3,5-dimethyl-4-methoxy)phenyl-5-fluoro-2,4-pyrimidinediamine

LCMS: purity: 96.03%; MS (m/e): 472.68 (MH+); ¹H NMR (DMSO-d₆): δ 0.90(m, 4H), 2.15 (s, 6H), 2.43 (m, 1H), 3.60 (s, 3H), 4.14 (d, J=6.3 Hz,2H), 7.23 (s, 2H), 7.27 (d, J=8.4 Hz, 2H), 7.57 (t, J=6.3 Hz, 1H), 7.74(d, J=8.4 Hz, 2H), 8.04 (d, J=3.9 Hz, 1H), 8.93 (s, 1H), 9.26 (s, 1H);¹⁹F NMR (282 MHz, DMSO-d₆): δ −164.70.

II-42:N4-(4-cyclopropylsulfonylaminomethyl)phenyl-N2-(3,5-dimethyl-4-methoxy)phenyl-5-methyl-2,4-pyrimidinediamine

LCMS: purity: 99.89%; MS (m/e): 468.27 (MH+); ¹H NMR (DMSO-d₆): δ 0.90(m, 4H), 2.09 (s, 3H), 2.11 (s, 6H), 2.43 (m, 1H), 3.58 (s, 3H), 4.14(d, J=6.3 Hz, 2H), 7.24 (s, 2H), 7.26 (d, J=10.8 Hz, 2H), 7.57 (t, J=6.3Hz, 1H), 7.66 (d, J=8.4 Hz, 2H), 7.83 (s, 1H), 8.19 (s, 1H), 8.70 (s,1H).

II-43:5-chloro-N4-(4-cyclopropylsulfonylaminomethyl)phenyl-N2-(3,5-dimethyl-4-methoxy)phenyl-2,4-pyrimidinediamine

LCMS: purity: 96.61%; MS (m/e): 488.79 (MH+); ¹H NMR (DMSO-d₆): δ 0.91(m, 4H), 2.10 (s, 6H), 3.58 (s, 3H), 4.16 (d, J=6.6 Hz, 2H), 7.18 (s,2H), 7.28 (d, J=8.4 Hz, 2H), 7.60 (t, J=5.7 Hz, 1H), 7.61 (d, J=7.8 Hz,2H), 8.08 (s, 1H), 8.74 (s, 1H), 9.07 (s, 1H).

II-44:N4-(3-cyclopropylsulfonylaminomethyl)phenyl-N2-(3,5-dimethyl-4-methoxy)phenyl-5-methyl-2,4-pyrimidinediamine

LCMS: purity: 91.20%; MS (m/e): 468.10 (MH+); ¹H NMR (DMSO-d₆): δ 0.87(m, 4H), 2.09 (s, 9H), 2.45 (m, 1H), 3.57 (s, 3H), 4.15 (d, J=6.0 Hz,2H), 7.02 (d, J=8.1 Hz, 1H), 7.25 (s, 2H), 7.26 (m, 1H), 7.59 (s, 2H),7.71 (d, J=7.8 Hz, 1H), 7.84 (s, 1H), 8.27 (s, 1H), 8.65 (s, 1H).

II-45:5-Chloro-N4[4-(N-cyclopropylsulfonylamino)ethylphenyl]-N2-[4-phenyltrifluoromethyl sulfone]-2,4-pyrimidinediamine

LCMS: purity: 98%; MS (m/z): [M+H]⁺=576; ¹H NMR (300 MHz, d6-DMSO):0.96-0.911 (d, J=7.43 Hz, 4H), 2.52-2.49 (m, 4H), 3.25-3.19 (m, 1H),7.29-7.18 (m, 4H), 7.55-7.50 (m, 2H), 7.83-7.78 (m, 2H), 8.03-7.98 (m,2H), 9.11-9.09 (d, J=5.7 Hz, 1H), 10.26-10.24 (d, J=6.3, 1H).

II-46:5-Chloro-N4[4-(N-cyclopropylsulfonylamino)ethylphenyl]-N2-[4-(2,6-dimethyl-methoxy)phenyl]-2,4-pyrimidinediamine

LCMS: purity: 98%; MS (m/z): [M+H]⁺=502; ¹H NMR (300 MHz, d6-DMSO):0.66-0.614 (m, 4H), 1.81-1.80 (d, J=2.5 Hz, 6H), 2.26-2.21 (m, 4H), 2.90(b, 1H), 3.07-3.02 (m, 4H), 6.92-6.89 (m, 4H), 7.27-7.23 (m, 2H),7.79-7.78 (m, 1H), 8.84-8.43 (d, J=2.2 Hz, 1H), 8.79 (b, 1H).

II-47:5-Chloro-N4[4-(N-cyclopropylsulfonylamino)ethylphenyl]-N2-[4-(2,6-dimethyl-ethoxy)phenyl]-2,4-pyrimidinediamine

LCMS: purity 98%; MS (m/z): [M+H]⁺=516; ¹H NMR (300 MHz, d6-DMSO):0.93-0.89 (m, 4H), 1.34-1.28 (m, 3H), 2.1-2.08 (d, J=4.4 Hz, 6H),2.50-2.49 (d, J=1.65 Hz, 4H), 3.22-3.16 (m, 1H), 3.74-3.70 (m, 2H),7.20-7.17 (m, 4H), 7.55-7.52 (d, J=8.25 Hz, 2H), 8.08-8.07 (d, J=4.68Hz, 1H), 8.73-8.71 (d, J=4.4 Hz, 1H), 9.07-9.06 (d, J=4.13 Hz, 1H).

II-48:5-Chloro-N4[4-(N-cyclopropylsulfonylamino)ethylphenyl]-N2-[4-(2,6-dimethyl-isopropoxy)phenyl]-2,4-pyrimidinediamine

LCMS: purity; 98%; MS (m/z): [M+H]⁺=530; ¹H NMR (300 MHz, d6-DMSO):0.92-0.88 (m, 4H), 1.20-1.17 (m, 6H), 2.06 (d, J=2.7 Hz, 6H), 2.49 (tr,J=3.5 Hz, 4H), 3.18 (m, 1H), 4.01 (m, 1H), 7.17-7.14 (m, 5H), 7.54-7.50(m, 2H), 8.06 (d, J=2.7 Hz, 1H), 8.69 (s, 1H), 9.03 (s, 1H).

II-49:5-Chloro-N4[4-(N-cyclopropylsulfonylamino)ethylphenyl]-N2-[4-(2,6-dimethyl-ethoxymorphlino)phenyl]-2,4-pyrimidinediamine)

LCMS: purity: 98%; MS (m/z): [M+H]⁺=601; ¹H NMR (300 MHz), d6-DMSO)0.92-0.89 (m, 4H), 2.10-2.09 (m, 6H), 3.31-3.14 (m, 11H), 3.66 (b, 4H),3.82 (b, 2H), 7.20-7.16 (m, 5H) 7.53-7.50 (m, 2H), 8.10-8.05 (m, 1H),8.71 (b, 1H), 9.07 (b, 1H).

II-50:5-Chloro-N4[4-(N-cyclopropylsulfonylamino)ethylphenyl]-N2-[4-(6-methoxy-2-methyl-methoxy)phenyl]-2,4-pyrimidinediamine

LCMS: purity; 98%; MS (m/z): [M+H]⁺=518; ¹H NMR (300 MHz, d6-DMSO):0.66-0.61 (m, 4H), 1.80-1.78 (m, 3H), 2.27-2.21 (m, 2H), 2.92 (d, J=5.8Hz, 1H), 3.06-3.05 (m, 2H), 3.28-3.27 (m, 3H), 3.33-3.32 (m, 3H),6.78-6.76 (m, 2H), 6.91-6.88 (m, 4H), 7.28-7.25 (m, 1H), 7.82-7.81 (m,1H), 8.46 (b, 1H), 8.81 (b, 1H).

II-51:5-Chloro-N4[4-(N-cyclopropylsulfonylamino)ethylphenyl]-N2-[4-(4-methylpiperazino)phenyl]-2,4-pyrimidinediamine

LCMS: purity; 95%; MS (m/z): [M+H]⁺=542; ¹H NMR (300 MHz, d6-DMSO):0.65-0.60 (m, 4H), 1.92 (s, 3H), 2.26-2.13 (m, 8H), 2.75-2.72 (m, 4H),2.95-2.90 (m, 1H), 6.49 (d, J=9.1 Hz, 2H), 6.91 (d, J=8.5 Hz, 3H), 7.13(d, J=8.8 Hz, 2H), 7.29 (d, J=8.3H z, 2H), 7.75 (s, 1H), 8.38 (b, 1H),8.72 (b, 1H).

II-52:5-Chloro-N4[4-(N-cyclopropylsulfonylamino)ethylphenyl]-N2-[4-(4-methylpiperazino)-2-methylphenyl]-2,4-pyrimidinediamine

LCMS: purity; 98%: MS (m/z): [M+H]⁺=556; ¹H NMR (300 MHz, d6-DMSO):0.68-0.65 (m, 4H), 1.88 (s, 3H), 2.25 (s, 3H), 3.07-2.93 (b, 13H),6.58-6.53 (m, 2H), 6.79 (d, J=8.5 Hz, 2H), 6.94-6.87 (m, 2H), 7.32 (d,J=8.3 Hz, 1H), 7.71 (s, 1H), 7.87 (s, 1H), 8.25 (d, J=28.6 Hz, 2H).

II-53:5-Chloro-N4[4-(N-cyclopropylsulfonylamino)ethylphenyl]-N2-[4-(4-methylpiperazino)pyrido]-2,4-pyrimidinediamine

LCMS: purity; 98%: MS (m/z); [M+H]⁺=543; ¹H NMR (300 MHz, d6-DMSO):0.70-0.68 (m, 4H), 2.31-2.27 (m, 3H), 3.022.88 (m, 9H), 3.37 (b, 4H),6.60-6.55 (m, 1H), 6.99-6.92 (m, 3H), 7.34 (d, J=7.4 Hz, 2H), 7.64 (d,J=8.8 Hz, 1H), 7.91-7.83 (m, 1H), 8.05 (b, 1H), 8.50 (b, 1H), 8.88 (b,1H).

II-54:5-Chloro-N4[4-(N-cyclopropylsulfonylamino)ethylphenyl]-N2-[4-(4-propylpiperazino)-2-trifluoromethylphenyl]-2,4-pyrimidinediamine

LCMS: Purity; 98%: MS (m/z); [M+H]⁺=638; ¹H NMR (300 MHz, d6-CDCl₃):1.14-0.91 (m, 8H), 1.88-1.79 (m, 2H), 2.14-2.35 (m, 1H), 3.01-2.90 (m,8H), 3.47-3.41 (m, 5H), 7.12 (d, J=3.3 Hz, 1H), 7.28-7.20 (m, 2H),7.40-7.36 (m, 2H), 7.50-7.48 (m, 1H), 7.91-7.82 (m, 2H), 8.30 (d, J=3.3Hz, 1H), 8.52 (b, 1H).

II-55:5-Chloro-N4[4-(N-cyclopropylsulfonylamino)ethylphenyl]-N2-[4-(4-methylsulfonylpiperazino)-2-trifluoromethylphenyl]-2,4-pyrimidinediamine

LCMS: purity; 98%: MS (m/z); [M+H]+=674; ¹H NMR (300 MHz, d6-DMSO):0.50-0.47 (m, 4H), 2.07 (tr, J=3.6 Hz, 3H), 2.37 (b, 2H), 2.51-2.47 (m,3H), 2.77 (b, 4H), 2.89-2.86 (m, 4H), 6.78-6.73 (m, 3H), 7.01 (b, 1H),7.13-7.09 (m 2H), 7.45 (b, 2H), 7.71 (d, J=3.6 Hz, 1H), 8.40 (b, 1H),9.09 (b, 1H).

II-56:5-Chloro-N4[4-(N-cyclopropylsulfonylamino)ethylphenyl]-N2-[4-(4-methylpiperazino)-2-fluorophenyl]-2,4-pyrimidinediamine

LCMS: Purity; 98%; MS (m/z); [M+H]⁺=560; ¹H NMR (300 MHz, d6-CDCl₃):1.00-0.95 (m, 2H), 1.15-1.130 (m, 2H), 2.42-2.35 (m, 2H), 2.92-2.84 (m,6H), 3.46-3.31 (m, 8H), 6.83-6.77 (m, 2H), 7.05 (d, J=8.5 Hz, 2H)7.24-7.20 (m, 2H), 7.46-7.39 (m, 2H), 7.85 (tr, J=10.2 Hz, 1H), 8.24 (b,1H), 9.13 (b, 1H).

II-57:5-Chloro-N4[4-(N-cyclopropylsulfonylamino)ethylphenyl]-N2-[4-(4-ethylpiperazino)-2-trifluoromethylphenyl]-2,4-pyrimidinediamine

LCMS: purity; 98%: MS (m/z); [M+H]⁺=624; ¹H NMR (300 MHz, d6-CDCl₃):0.95-0.91 (m, 2H), 1.13-1.11 (m, 2H), 1.44 (tr, J=14.6 Hz, 3H),2.41-2.34 (m, 1H), 2.95-2.91 (m, 4H), 3.19-3.04 (m, 4H), 3.45-3.41 (m,4H), 3.66 (b, 2H), 5.82 (b, 1H), 7.27-7.17 (m, 3H), 7.40-7.37 (m, 2H),7.48 (b, 1H), 7.91-7.86 (m, 2H), 8.21 (d, J=1.9 Hz, 1H), 9.05 (b, 1H).

II-58:5-Chloro-N4[4-(N-cyclopropylsulfonylamino)ethylphenyl]-N2-[4-biphenyl]-2,4-pyrimidinediamine

LCMS: purity; 98%: MS (m/z); [M+H]⁺=520; ¹H NMR (300 MHz d6-, CDCl₃):0.91 (d, J=5.5 Hz, 2H), 1.07 (b, 2H), 2.33-2.29 (m, 1H), 2.90 (tr,J=14.0 Hz, 2H), 3.38 (tr, J=12.6 Hz, 2H), 6.35 (b, 1H), 7.30-7.20 (m,3H), 7.67-7.37 (m, 10H), 8.02 (d, J=4.4 Hz, 1H), 8.29 (b, 1H).

II-59:N4-[4-(N-cyclopropylsulfonylamino)ethylphenyl)]-5-methyl-N2-[4-trifluoromethylsulfonylphenyl]-2,4-pyrimidinediamine

¹H NMR (300 MHz, d6-CDCl₃) 1.00-0.93 (m, 2H), 1.14-1.09 (m, 2H), 2.18(s, 3H), 2.40-2.35 (m, 1H), 2.93-2.89 (tr, J=14.9 Hz, 2H) 3.41-3.34 (m,2H), 6.23 (tr, J=11.6 Hz, 1H), 7.24 (d, J=8.3 Hz, 2 Hz), 7.51-7.42 (m,2H), 7.72-7.67 (m, 2H), 7.957.87 (m, 2H), 8.08 (s, 1H), 9.44 (b, 1H).LCMS: purity; 98%; MS (m/z); [M+H]⁺=556

II-60:N-(4-(2-(4-(4-(bicyclo[2.2.1]heptan-2-yl)piperazin-1-yl)phenylamino)-5-methylpyrimidin-4-ylamino)benzyl)cyclopropanesulfonamide

LCMS: purity; 98%; MS (m/z); [M+H]⁺=588; ¹H NMR (300 MHz, d6-CDCl₃):0.93 (d, J=8 Hz, 2H), 1.15 (d, J=3.3 Hz, 2H), 1.60-1.44 (m, 4H),1.99-1.92 (m, 1H), 2.08 (s, 3H), 2.42-2.33 (m, 1H), 2.54 (b, 1H), 2.91(b, 1H), 3.23-3.14 (m, 3H), 3.47-3.38 (m, 3H), 4.27-3.75 (b, 8H),6.78-6.75 (m, 1H), 7.44-7.19 (m, 9H), 8.45 (d, J=2H, 1H), 11.08 (b, 1H).

II-61:N-(4-(2-(4-(4-(bicyclo[2.2.1]heptan-2-yl)piperazin-1-yl)phenylamino)-5-chloropyrimidin-4-ylamino)benzyl)cyclopropanesulfonamide

LCMS: purity; 98%, MS (m/z); [M+H]⁺=608; ¹H NMR (300 MHz, d6-CDCl₃):0.90-0.86 (m, 2H), 1.09-1.07 (m, 2H), 1.37-1.32 (b, 4H), 1.80 (m, 1H),2.41-2.19 (m, 3H), 2.66-2.57 (m, 3H), 3.195-3.17 (m, 3H), 4.28-4.24 (m,8H), 6.86-6.82 (m, 2H), 6.98 (d, J=4 Hz, 1H), 7.45-7.30 (m, 4H),7.61-7.57 (m, 2H), 7.77-7.70 (m, 1H), 7.97-7.96 (m, 1H), 8.07-8.05 (m,1H).

II-62:N4-[4-(N-cyclopropylsulfonylamino)ethylphenyl)]-5-methyl-N2-[4-(2,6-dimethyl)methoxyphenyl]-2,4-pyrimidinediamine

LCMS: purity; 98%; MS (m/z); [M+H]⁺=482; ¹HNMR (300 MHz, d6-CDCl₃):0.83-0.79 (m, 2H), 0.98 (b, 2H), 2.02-1.93 (m, 9H), 2.22-2.18 (m, 1H),2.73-2.69 (m, 2H), 3.23 (b, 2H), 3.52 (tr, J=3.6 Hz, 3H), 6.79 (b, 1H),7.07-6.97 (m, 5H), 7.36-7.28 (m, 3H), 10.89 (b, 1H).

II-63:N4-[4-(N-cyclopropylsulfonylamino)ethylphenyl)]-5-methyl-N2-[4-(2,6-dimethyl)ethoxyphenyl]-2,4-pyrimidinediamine

LCMS: purity 98%, MS (m/z); [M+H]⁺=496; ¹HNMR (300 MHz, d6-CDCl₃):1.00-0.96 (m, 2H), 1.16-1.14 (m, 2H), 1.42-1.37 (m, 3H), 2.16 (d, J=20.6Hz, 9H), 2.40-2.34 (m, 1H), 2.89-2.85 (m, 2H), 3.40 (b, 2H), 3.82-3.75(m, 2H), 7.24-7.11 (m, 5H), 7.53-7.46 (m, 3H), 8.40 (d, J=2.5 Hz, 1H),11.06 (b, 1H).

II-64:N4-[4-(N-cyclopropylsulfonylamino)ethylphenyl)]-5-methyl-N2-[4-(2,6-dimethyl)isopropoxyphenyl]-2,4-pyrimidinediamine

LCMS: purity; 98%; MS (m/z); [M+H]⁺=510; ¹HNMR (300 MHz, d6-CDCl₃):0.990.94 (m, 2H), 1.181.14 (m, 2H), 1.34-1.27 (m, 6H), 2.17 (d, J=18.7Hz, 9H), 2.38-2.34 (m, 1H), 2.89 (tr, J=13.8 Hz, 2H), 3.40 (b, 2H),4.16-4.08 (m, 1H), 6.77 (s, 1H), 7.24-7.15 (m, 5H), 7.58-7.49 (m, 3H),8.45 (s, 1H), 10.78 (b, 1H).

II-65:N4-[4-(N-cyclopropylsulfonylamino)ethylphenyl)]-5-methyl-N2-[4-(2,6-dimethyl)ethoxymorpholino-phenyl]-2,4-pyrimidinediamine

LCMS: purity; 98%; MS (m/z); [M+H]⁺=581; ¹HNMR (300 MHz, d6-CDCl₃): 0.94(d, J=7.98 Hz, 2H), 1.11 (d, J=2.2 Hz, 2H), 2.17 (d, J=12.1 Hz, 9H),2.31-2.27 (m, 1H), 2.90 (tr, J=12.9 Hz, 2H), 2.98 (b, 2H), 3.11 (tr,J=10.2 Hz, 2H), 3.40 (b, 2H), 4.01-3.88 (m, 8H), 6.99 (s, 1H), 7.24-7.14(m, 4H), 7.46 (d, J=8.5 Hz, 2H), 7.58 (s, 1H), 8.35 (s, 1H), 11.31 (b,1H).

II-66:N4-[4-(N-cyclopropylsulfonylamino)ethylphenyl)]-5-methyl-N2-[4-(6-methoxy-2-methyl)methoxyphenyl]-2,4-pyrimidinediamine

LCMS: purity; 98% MS (m/z); [M+H]+=498; ¹HNMR (300 MHz, d6-CDCl₃): 0.99(d, J=8.0 Hz, 2H), 1.16 (b, 2H), 2.14 (b, 6H), 2.40-2.36 (m, 1H), 2.88(tr, J=13.2 Hz, 2H), 3.40 (b, 2H), 3.60 (s, 3H), 3.74 (s, 3H), 6.93 (d,J=24.5H, 2H), 7.16-7.07 (m, 3H), 7.56-7.45 (m, 3H), 8.39 (s, 1H), 10.97(b, 1H).

II-67:N4-[4-(N-cyclopropylsulfonylamino)ethylphenyl)]-5-methyl-N2-[4-(4-methylpiperazino)phenyl]-2,4-pyrimidinediamine

LCMS: purity; 98%; MS (m/z); [M+H]+=522; ¹HNMR (300 MHz, d6-DMSO): 0.94(b, 4H), 2.15 (tr, J=3.0 Hz, 3H), 2.51-2.49 (m, 4H) 2.93-2.81 (m, 4H),3.22 (b, 4H), 3.50 (b, 4H), 6.92 (d, J=6.6 Hz, 2H), 7.32-7.19 (m, 4H),7.51-7.47 (m, 2H), 7.82 (b, 1H), 9.50 (b, 1H), 10.12 (b, 1H).

II-68:N4-[4-(N-cyclopropylsulfonylamino)ethylphenyl)]-5-methyl-N2-[4-(4-methylpiperazino)-2-methylphenyl]-2,4-pyrimidinediamine

LCMS: purity 98%; MS (m/z); [M+H]⁺=536; ¹HNMR (300 MHz, d6-CDCl₃):0.92-0.92 (m, 2H), 1.06 (b, 2H), 2.10 (s, 3H), 2.18 (s, 3H) 2.34-2.29(m, 1H), 2.76 (b, 4H), 2.89 (s, 3H), 3.28 (b, 4H), 3.79-3.66 (m, 4H),6.80-6.74 (m, 2H), 6.93 (d, J=8.5 Hz, 2 Hz), 7.23-7.13 (m, 4H), 7.45 (s,1H), 10.90 (b, 1H).

II-69:N4-[4-(N-cyclopropylsulfonylamino)ethylphenyl)]-5-methyl-N2-[4-(4-methylpiperazino)pyrido]-2,4-pyrimidinediamine

LCMS: purity; 98%; MS (m/z); [M+H]⁺=523; ¹HNMR (300 MHz, d6-CDCl₃):0.93-0.91 (d, J=7.4 Hz, 2H), 1.05 (b, 2H), 2.18 (s, 3H), 2.36-2.34 (m,1H), 2.90-2.86 (b, 7H), 3.36-3.34 (b, 8H), 6.65-6.58 (m, 2H), 7.20 (d,J=8.2 Hz, 2H), 7.40 (d, J=8.3 Hz, 2H), 7.53 (s, 1H), 7.68 (b, 1H), 8.24(b, 1H), 9.30 (b, 1H), 11.36 (b, 1H).

II-70:N4-[4-(N-cyclopropylsulfonylamino)ethylphenyl)]-5-methyl-N2-[4-(4-methylpiperazino)-2-trifluoromethylphenyl]-2,4-pyrimidinediamine

LCMS: purity; 98%; MS (m/z); [M+H]⁺=590; ¹HNMR (300 MHz, d6-CDCl₃): 0.96(d, J=4.5 Hz, 2H), 1.09 (b, 2 Hz), 2.17 (s, 3H), 2.39-2.38 (m, 1H),2.92-2.87 (m, 5H), 3.06-2.98 (m, 2H), 3.41-3.35 (m, 4H), 3.61-3.58 (m,4H), 7.32-7.18 (m, 5H), 7.46 (s, 1H), 7.55 (d, J=4.4 Hz, 2H), 7.78 (d,6.8 Hz, 1H), 8.06 (s, 1H), 11.83 (b, 1H).

II-71:N4-[4-(N-cyclopropylsulfonylamino)ethylphenyl)]-5-methyl-N2-[4-(4-propylpiperazino)-2-trifluoromethylphenyl]-2,4-pyrimidinediamine

LCMS: purity; 98%; MS (m/z); [M+H]⁺=618; ¹HNMR (300 MHz, d6-CDCl₃):1.11-0.94 (m, 7H), 1.87-1.82 (m, 3H), 2.19 (s, 3H), 2.41-2.39 (m, 1H),3.03-2.90 (m, 8H), 3.43-3.40 (m, 3H), 3.67 (d, J=10.2 Hz, 2H), 6.20 (b,1H), 7.32-7.17 (m, 6H), 7.53 (d, J=9.6 Hz, 2H), 7.83 (d, J=7.4 Hz, 1H),11.85 (b, 1H).

II-72:N4-[4-(N-cyclopropylsulfonylamino)ethylphenyl)]-5-methyl-N2-[4-(4-sulfonylmethyl-piperazino)-2-trifluoromethylphenyl]-2,4-pyrimidinediamine

LCMS: Purity; 98%; MS (m/z); [M+H]⁺=654; ¹HNMR (300 MHz, d6-CDCl₃): 0.95(d, J=6.3 Hz, 2H), 1.08 (b, 2H), 2.20 (s, 3H), 2.38-2.35 (m, 1H),2.97-2.85 (m, 9H), 3.37-3.33 (b, 6H), 6.57-6.53 (m, 1H), 7.22-7.19 (m,2H), 7.42 (d, J=8.3 Hz, 2H), 7.54 (s, 1H), 7.68-7.62 (m, 2H), 7.75 (s,1H), 9.16 (b, 1H), 11.28 (b, 1H).

II-73:N4-[4-(N-cyclopropylsulfonylamino)ethylphenyl)]-5-methyl-N2-[4-(4-methylpiperazino)-2-fluorophenyl]-2,4-pyrimidinediamine

LCMS: purity; 95%; MS (m/z); [M+H]⁺=540; ¹HNMR (300 MHz, d6-CDCl₃):0.98-0.95 (m, 2H), 1.13-1.11 (m, 2H), 2.17 (s, 3H), 2.42-2.37 (m, 1H),3.08-2.85 (m, 6H), 3.42-3.27 (m, 5H), 3.65-3.61 (b, 4H), 5.63 (b, 1H),6.81-6.75 (m, 2H), 7.35-7.15 (m, 5H), 7.52 (s, 1H), 8.02 (b, 1H), 11.70(s, 1H).

II-74:N4-[4-(N-cyclopropylsulfonylamino)ethylphenyl)]-5-methyl-N2-[4-(4-ethylpiperazino)-2-trifluoromethylphenyl]-2,4-pyrimidinediamine

¹HNMR (300 MHz, d6-CDCl₃): 0.95-0.88 (m, 2H), 1.12-1.10 (m, 2H),1.43-1.38 (m, 3H), 2.15 (s, 3H), 2.40-2.36 (m, 1H), 2.94 (tr, J=13.8 Hz,4H), 3.13-3.09 (m, 4H), 3.41 (b, 4H), 3.61 (b, 2H), 6.08 (b, 1H), 7.1(b, 1H), 7.59-7.23 (m, 6H), 7.86 (d, J=8.5 Hz, 1H), 8.38 (s, 1H), 11.04(b, 1H). LCMS: purity; 95%; MS (m/z); [M+H]⁺=604.

II-75:N4-[4-(N-cyclopropylsulfonylamino)ethylphenyl)]-5-methyl-N2-[4-biphenyl]-2,4-pyrimidinediamine

LCMS: purity; 98%; MS (m/z); [M+H]⁺=500; ¹HNMR (300 MHz, d6-CDCl₃):0.95-0.88 (m, 2H), 1.13-1.09 (m, 2H), 2.13 (s, 3H), 2.34-2.26 (m, 1H),2.91 (tr, J=13.5 Hz, 2H), 3.43 (d, J=5.8 Hz, 2H), 6.38 (s, 1H),6.75-6.72 (m, 1H), 7.62-7.18 (m, 13H), 7.83 (s, 1H), 8.47 (b, 1H).

II-76:N-(3-(2-(4-(4-(bicyclo[2.2.1]heptan-2-yl)piperazin-1-yl)phenylamino)-5-chloropyrimidin-4-ylamino)-5-methylbenzyl)cyclopropanesulfonamide

LCMS: Purity; 98%; MS (m/z); [M+H]⁺=622; ¹HNMR (300 MHz, d6-CDCl₃): 0.94(d, J=7.7 Hz, 2H), 1009 (b, 2H), 1.49 (s, 3H), 1.62-1.58 (b, 2H),1.75-1.70 (b, 1H), 1.98-1.92 (m, 2H), 2.29 (s, 3H), 2.38-2.34 (m, 1H),2.59 (b, 1H), 3.13-3.01 (m, 3H), 3.57-3.44 (m, 6H), 3.85 (d, J=11.6 Hz,1H), 4.16 (b, 2H), 6.89 (d, J=8.8 Hz, 2H), 7.10 (b, 2H), 7.24-7.22 (m,2H), 7.36-7.33 (m, 2H), 7.78-7.75 (m, 2H), 11.70 (b, 1H).

II-77:N-(3-(2-(4-(4-(bicyclo[2.2.1]heptan-2-yl)piperazin-1-yl)phenylamino)-5-methylpyrimidin-4-ylamino)-5-methylbenzyl)cyclopropanesulfonamide

LCMS: purity; 98%; MS (m/z); [M+H]⁺=602; ¹HNMR (300 MHz, d6-CDCl₃): 0.89(d, J=6.3 Hz, 2H), 1.08 (b, 2H), 1.48 (s, 3H), 1.60-1.54 (m, 2 Hz),1.75-1.71 (b, 1H), 1.98-1.94 (b, 2H), 2.18 (s, 3H), 2.37-2.31 (m, 5H),2.61 (b, 1H), 3.52-3.03 (b, 9H), 4.21 (d, J=5.8 Hz, 2H), 6.76 (d, J=8.8Hz, 2H), 6.96 (tr, J=11.3 Hz, 1H), 7.10 (s, 1H) 7.29 (s, 2H), 7.40-7.37(d, J=8.0 Hz, 1H), 7.50-7.45 (m, 2H), 9.19 (s, 1H), 11.26 (b, 1H).

II-78:N-(4-(2-(4-(4-(bicyclo[2.2.1]heptan-2-yl)piperazin-1-yl)-3-fluorophenylamino)-5-methylpyrimidin-4-ylamino)benzyl)cyclopropanesulfonamide

LCMS: purity; 98%; MS (m/z); [M+H]⁺=606; ¹HNMR (300 MHz, d6-CDCl₃): 0.99(d, J=6.6 Hz, 2H), 1.17 (b, 2H), 1.49 (b, 3H), 1.63 (b, 3H) 1.98-1.95(b, 2H), 2.15 (s, 3H), 2.38 (b, 1H), 2.49 (b, 1H) 2.69-2.61 (m, 2H),3.55-3.13 (m, 9H), 4.31 (s, 1H), 6.83 (m, 1H), 7.38-7.17 (m, 7H), 7.59(s, 1H), 8.25 (s, 1H), 11.26 (b, 1H).

II-79:N-(4-(2-(4-(4-(bicyclo[2.2.1]heptan-2-yl)piperazin-1-yl)-3-fluorophenylamino)-5-chloropyrimidin-4-ylamino)benzyl)cyclopropanesulfonamide

LCMS: purity; 98%; MS (m/z); [M+H]⁺=626; ¹HNMR (300 MHz, d6-CDCl₃): 0.97(d, J=6.3 Hz, 2H), 1.15 (b, 2H), 1.50 (s, 3H), 1.63 (b, 2H), 1.89 (b,1H), 2.42-2.40 (b, 2H), 2.642.63 (m, 2H), 3.363.34 (m, 3H), 3.813.80 (m,8H), 4.31 (s, 1H), 6.90 (tr, J=18.2 Hz, 1H), 7.16 (d, 9.1 Hz, 1H),7.37-7.29 (m, 4H), 7.48-7.45 (m, 2H), 7.96 (s, 1H), 11.26 (b, 1H).

II-80:5-Chloro-N2-(3-chloro-4-methoxy-5-methylphenyl]-N4-[4-(N-cyclopropylsulfonylamino)methylphenyl]-2,4-pyrimidinediamine

LCMS: Purity: 99%; MS (m/e): 509 (MH⁺); ¹H NMR (DMSO-d6): δ 9.34 (s,1H), 8.88 (s, 1H), 7.62-7.57 (m, 4H), 7.33-7.30 (m, 3H), 4.15 (d, 2H,J=6.3 Hz), 3.65 (s, 3H), 2.44-2.41 (m, 1H), 2.12 (s, 3H), 0.89-0.86 (m,4H).

II-81:N4-[4-(N-Cyclopropylsulfonylamino)methylphenyl]-N2-(3,5-dimethyl-4-methoxyphenyl)-5-ethyl-2,4-pyrimidinediamine

LCMS: Purity: 99%; MS (m/e): 482 (MH⁺); ¹H NMR (DMSO-d6): δ 8.71 (s,1H), 8.22 (s, 1H), 7.84 (s, 1H), 7.64 (d, 2H, J=8.5 Hz), 7.57 (t, 1H,J=6.4 Hz), 7.34 (d, 1H, J=8.5 Hz), 7.24 (s, 2H), 4.13 (d, 2H, J=6.3 Hz),3.56 (s, 3H), 2.52 (qt, 2H, J=7.3 Hz), 2.45-2.42 (m, 1H), 2.09 (s, 6H),1.13 (t, 3H, J=7.3 Hz), 0.89-0.86 (m, 4H).

II-82:N4-[4-(N-Cyclopropylsulfonylamino)methylphenyl]-N2-(3,4-dimethoxy-5-methylphenyl)-5-ethyl-2,4-pyrimidinediamine

LCMS: Purity: 99%; MS (m/e): 498 (MH⁺); ¹H NMR (DMSO-d6): δ 8.74 (s,1H), 8.24 (s, 1H), 7.85 (s, 1H), 7.65 (d, 1H, J=8.5 Hz), 7.57 (t, 1H,J=6.9 Hz), 7.25 (d, 2H, J=8.2 Hz), 7.12 (d, 2H, J=9.1 Hz), 4.13 (d, 2H,J=6.1 Hz), 3.58 (s, 3H), 3.56 (s, 3H), 2.54 (qt, 2H, J=7.3 Hz), 2.06 (s,3H), 1.14 (t, 3H, J=7.3 Hz), 0.89-0.88 (m, 4H).

II-83:N2-(3-Chloro-4-methoxy-5-methylphenyl)-N4-[4-(N-cyclopropylsulfonylamino)methylphenyl]-5-ethyl-2,4-pyrimidinediamine

LCMS: Purity: 99%; MS (m/e): 503 (MH⁺); ¹H NMR (DMSO-d6): δ 8.99 (s,1H), 8.31 (s, 1H), 7.87 (s, 1H), 7.63-7.56 (m, 4H), 7.37 (s, 1H), 7.29(d, 1H, J=8.5 Hz), 4.15 (d, 2H, J=5.4 Hz), 3.65 (s, 3H), 2.54 (qt, 2H,J=7.6 Hz), 2.13 (s, 3H), 1.14 (t, 3H, J=7.6 Hz), 0.89-0.86 (m, 4H).

II-84:N4-[4-(N-Cyclopropylsulfonylamino)methylphenyl]-N2-(3,5-dichloro-4-methoxyphenyl)-5-ethyl-2,4-pyrimidinediamine

LCMS: Purity: 99%; MS (m/e): 523 (MH⁺); ¹H NMR (DMSO-d6): δ: 9.23 (s,1H), 8.39 (s, 1H), 7.91 (s, 1H), 7.78 (s, 2H), 7.57-7.56 (m, 3H),7.32-7.29 (m, 2H), 4.14 (d, 2H, J=6.1 Hz), 3.72 (s, 3H), 2.54 (qt, 2H,J=7.0 Hz), 1.14 (t, 3H, J=7.0 Hz), 0.90-0.87 (m, 4H).

II-85:N4-[4-(N-Cyclopropylsulfonylamino)methylphenyl]-5-ethyl-N2-(3-,4,5-trimethoxylphenyl)-2,4-pyrimidinediamine

LCMS: Purity: 98%; MS (m/e): 514 (MH⁺); ¹H NMR (DMSO-d6): δ 8.79 (s,1H), 8.25 (s, 1H), 7.87 (s, 1H), 7.66-7.55 (m, 3H), 7.24 (d, 2H, J=7.9Hz), 7.05 (s, 2H), 4.14 (d, 2H, J=6.1 Hz), 3.56 (s, 9H), 2.54 (qt, 2H,J=7.0 Hz), 1.14 (t, 3H, J=7.0 Hz), 0.90-0.87 (m, 4H).

II-86:N4-[4-(N-Cyclopropylsulfonylamino)methylphenyl]-5-ethyl-N2-[4-(4-methyl-1-piperazinyl)phenyl]-2,4-pyrimidinediamine

LCMS: Purity: 99%; MS (m/e): 522 (MH⁺); ¹H NMR (DMSO-d6): δ 8.71 (s,1H), 8.23 (s, 1H), 7.81 (s, 1H), 7.66-7.58 (m, 3H), 7.48 (d, 2H, J=8.8Hz), 7.27 (d, 2H, J=8.2 Hz), 6.77 (d, 2H, J=9.1 Hz), 4.17 (d, 2H, J=6.4Hz), 3.04 (s, 4H), 2.53-2.50 (m, 6H), 2.28 (s, 3H), 1.13 (t, 3H, J=7.3Hz), 0.88-0.86 (m, 4H).

II-87:N4-[4-(N-Cyclopropylsulfonylamino)methylphenyl]-N2-[4-(4,4-difluoro-1-piperidinyl)phenyl]-5-ethyl-2,4-pyrimidinediamine

LCMS: Purity: 99%; MS (m/e): 543 (MH⁺); ¹H NMR (DMSO-d6): δ 8.73 (s,1H), 8.24 (s, 1H), 7.82 (s, 1H), 7.65-7.57 (m, 3H), 7.49 (s, 2H, J=8.8Hz), 7.27 (d, 2H, J=8.2 Hz), 6.83 (d, 2H, J=8.8 Hz), 4.15 (d, 2H, J=6.1Hz), 3.20-3.16 (m, 4H), 2.55-2.51 (m, 3H), 2.08-1.98 (m, 4H), 1.13 (t,3H, J=7.6 Hz), 0.88-0.86 (m, 4H).

II-88:N4-[4-(N-Cyclopropylsulfonylamino)methylphenyl]-5-ethyl-N2-[4-(1-methyl-4-piperidinyl)pheny]-2,4-pyrimidinediamine

LCMS: Purity: 99%; MS (m/e): 521 (MH⁺); ¹H NMR (DMSO-d6): δ 8.87 (s,1H), 8.26 (s, 1H), 8.21 (s, 1H), 7.66-7.57 (m, 2H0, 7.56 (d, 2H, J=8.5Hz), 7.28 (d, 2H, J=8.2 Hz), 7.02 (d, 2H, J=8.2 Hz), 4.16 (d, 2H, J=5.8Hz), 2.91-2.94 (m, 2H), 2.52 (t, 2H, J=7.3 Hz), 2.47-2.45 (m, 1H), 2.29(s, 3H), 2.21-2.13 (m, 2H), 1.71-1.63 (m, 3H), 1.14 (t, 3H, J=7.3 Hz),0.89-0.86 (m, 4H).

II-89:N4-[4-(N-Cyclopropylsulfonylamino)methylphenyl]-5-ethyl-N2-[4-(4-ethyl-1-piperazinyl)phenyl]-2,4-pyrimidinediamine

LCMS: Purity: 99%; MS (m/e): 536 (MH⁺).

II-90:5-Chloro-N2-(3,5-dimethyl-5-methoxyphenyl)-N4-[(4-(dimethylamino)sulfonylamino)methylphenyl]-2,4-pyrimidinediamine

LCMS: Purity: 97%; MS (m/e): 492 (MH⁺); ¹H NMR (DMSO-d6): δ 9.67 (s,1H), 9.43 (s, 1H), 8.20 (s, 1H), 7.69 (t, 1H, J=5.8 Hz), 7.56 (d, 2H,J=8.5 Hz), 7.29 (d, 2H, J=8.5 Hz), 7.10 (s, 2H), 4.08 (d, 2H, J=5.8 Hz),3.58 (s, 3H), 2.63 (s, 6H), 2.09 (s, 6H).

II-91:5-Chloro-N2-(3,4-dimethoxy-5-methylphenyl)-N4-[(4-(dimethylamino)sulfonylamino)methylphenyl]-2,4-pyrimidinediamine

LCMS: Purity: 99%; MS (m/e): 508 (MH⁺); ¹H NMR (DMSO-d6): δ 9.86 (s,1H), 9.56 (s, 1H), 8.23 (s, 1H), 7.69 (t, 1H, J=5.8 Hz), 7.56 (d, 2H,J=8.2 Hz), 7.29 (d, 2H, J=8.2 Hz), 6.91 (s, 2H), 4.08 (d, 2H, J=5.8 Hz),3.62 9s, 3H), 3.57 (s, 3H), 2.63 (s, 6H), 2.06 (s, 3H).

II-92:5-Chloro-N2-(3-chloro-4,5-dimethoxyphenyl)-N4-[(4-(dimethylamino)sulfonylamino)methylphenyl]-2,4-pyrimidinediamine

LCMS: Purity: 99%; MS (m/e): 528 (MH⁺); ¹H NMR (DMSO-d6): δ 9.61 (s,1H), 9.18 (s, 1H), 8.20 (s, 1H), 7.68 (t, 1H, J=4.9 Hz), 7.57 (d, 2H,J=8.2 Hz), 7.37 (s, 1H), 7.29 (d, 2H, J=8.2 Hz), 7.13 (s, 1H), 4.07 (d,2H, J=4.9 Hz), 3.65 (s, 3H), 3.61 (s, 3H), 2.63 (s, 6H).

II-93:5-Chloro-N2-(3-chloro-4-methoxy-5-methylphenyl)-N4-[(4-(dimethylamino)sulfonylamino)methylphenyl]-2,4-pyrimidinediamine

LCMS: Purity: 99%; MS (m/e): 512 (MH⁺); ¹H NMR (DMSO-d6): δ: 9.76 (s,1H), 9.34 (s, 1H), 8.21 (s, 1H), 7.69 (t, 1H, J=4.9 Hz), 7.55-7.49 (m,3H), 7.33-7.27 (m, 3H), 4.08 (d, 2H, J=4.9 Hz), 3.66 (s, 3H), 2.63 (s,6H), 2.13 (s, 3H).

II-94:5-Chloro-N2-[3,5-dichloro-4-methoxyphenyl]-N4-[(4-(dimethylamino)sulfonylamino)methylphenyl]-2,4-pyrimidinediamine

LCMS: Purity: 99%; MS (m/e): 532 (MH⁺); ¹H NMR (DMSO-d6): δ 9.78 (s,1H), 9.19 (s, 1H), 8.21 (s, 1H), 7.67 (s, 2H), 7.53 (d, 2H, J=8.2 Hz),7.33 (d, 2H, J=8.2 Hz), 4.09 (d, 2H, J=4.9 Hz), 3.72 (s, 3H), 2.63 (s,6H).

II-95:5-Chloro-N4-[(4-(dimethylamino)sulfonylamino)methylphenyl]-N2-[3,4,5-trimethoxyphenyl)-2,4-pyrimidinediamine

LCMS: Purity: 99%; MS (m/e): 524 (MH⁺); ¹H NMR (DMSO-d6): δ 9.34 (s,1H), 9.01 (s, 1H), 8.14 (s, 1H), 7.68 (t, 1H, J=6.2 Hz), 7.60 (d, 2H,J=8.2 Hz), 7.25 (d, 2H, J=8.5 Hz), 6.92 (s, 2H), 4.07 (d, 2H, J=6.2 Hz),3.57 (s, 3H), 3.55 (s, 6H), 2.63 (s, 6H).

II-96:5-Chloro-N4-[(4-(dimethylamino)sulfonylamino)methylphenyl]-N2-[4-(4-methyl-1-piperazinyl)phenyl]-2,4-pyrimidinediamine

LCMS: Purity: 99%; MS (m/e): 532 (MH⁺).

II-97:5-Chloro-N4-[(4-(dimethylamino)sulfonylamino)methylphenyl]-N2-[4-(4,4-difluoro-1-piperidinyl)phenyl]-2,4-pyrimidinediamine

LCMS: Purity: 99%; MS (m/e): 553 (MH⁺); ¹H NMR (DMSO-d6): δ 9.32 (s,1H), 9.05 (s, 1H), 8.10 (s, 1H), 7.69 (t, 1H, J=5.8 Hz), 7.59 (d, 2H,J=7.9 Hz), 7.39 (d, 2H, J=8.5 Hz), 7.29 (d, 2H, J=7.9 Hz), 6.87 (d, 2H,J=8.8 Hz), 4.09 (d, 2H, J=5.8 Hz), 3.23 (br s, 4H), 2.64 (m, 6H),2.09-2.07 (m, 4H).

II-98:5-Chloro-N4-[(4-(dimethylamino)sulfonylamino)methylphenyl]-N2-[4-(1-methyl-4-piperidinyl)pheny]-2,4-pyrimidinediamine

LCMS: Purity: 99%; MS (m/e): 531 (MH⁺); ¹H NMR (DMSO-d6): δ 9.36 (s,1H), 8.91 (s, 1H), 8.12 (s, 1H), 7.69 (t, 1H, J=6.1 Hz), 7.61 (d, 2H,J=8.5 Hz), 7.53 (d, 2H, J=8.2 Hz), 7.29 (d, 2H, J=8.5 Hz), 7.04 (d, 2H,J=8.8 Hz), 4.09 (d, 2H, J=6.1 Hz), 3.48 (m, 2H), 3.05 (m, 2H), 2.80 (s,3H), 2.64 (s, 6H), 2.01-1.96 (m, 2H), 1.81-1.72 (m, 2H).

II-99:4-[(4-(Dimethylamino)sulfonylamino)methylphenyl]-N2-(3,5-dimethyl-4-methoxyphenyl)-5-methyl-2,4-pyrimidinediamine

LCMS: Purity: 99%; MS (m/e): 471 (MH⁺); ¹H NMR (DMSO-d6): δ 10.19 (s,1H), 9.68 (s, 1H), 7.85 (s, 1H), 7.71 (t, 1H, J=6.2 Hz), 7.52 (d, 2H,J=8.5 Hz), 7.33 (d, 2H, J=8.5 Hz), 7.02 (s, 2H), 4.09 (d, 2H, J=6.2 Hz),3.60 (s, 3H), 2.63 (s, 6H), 2.14 (s, 3H), 2.12 (s, 6H).

II-100:4-[(4-(Dimethylamino)sulfonylamino)methylphenyl]-N2-(3,4-dimethoxy-5-methylphenyl)-5-methyl-2,4-pyrimidinediamine

LCMS: Purity: 99%; MS (m/e): 487 (MH⁺); ¹H NMR (DMSO-d6): δ 10.21 (s,1H), 9.65 (s, 1H), 7.84 (s, 1H), 7.06 (t, 1H, J=6.2 Hz), 7.54 (d, 2H,J=8.5 Hz), 7.30 (d, 2H, J=8.2 Hz), 6.83 (s, 1H), 6.82 (s, 1H), 4.09 (d,2H, J=6.2 Hz), 3.65 (s, 3H), 3.58 (s, 3H), 2.63 (s, 6H), 2.14 (s, 3H),2.09 (s, 3H).

II-101:5-Methyl-N2-(3-chloro-4-methoxy-5-methylphenyl)-N4-[(4-(dimethylamino)sulfonylamino)methylphenyl]-2,4-pyrimidinediamine

LCMS: Purity: 99%; MS (m/e): 492 (MH⁺); ¹H NMR (DMSO-d6): δ 10.32 (s,1H), 9.70 (s, 1H), 7.89 (s, 1H), 7.70 (t, 1H, J=6.2 Hz), 7.50 (d, 2H,J=8.5 Hz), 7.39 (d, 1H, J=2.3 Hz), 7.34 (d, 2H, J=8.5 Hz), 7.16 (d, 1H,J=2.3 Hz), 4.09 (d, 1H, J=6.2 Hz), 3.69 (s, 3H), 2.63 (s, 6H), 2.16 (s,6H).

II-102:5-methyl-N2-[3,5-dichloro-4-methoxyphenyl]-N4-[(4-(dimethylamino)sulfonylamino)methylphenyl]-2,4-pyrimidinediamine

LCMS: Purity: 99%; MS (m/e): 512 (MH⁺); ¹H NMR (DMSO-d6): δ 10.65 (s,1H), 9.76 (s, 1H), 7.93 (s, 1H), 7.69 (t, 1H, J=6.2 Hz), 7.54 (s, 2H),7.48 (d, 2H, J=8.0 Hz), 7.36 (d, 2H, J=8.0 Hz), 4.10 (d, 2H, J=6.2 Hz),3.76 (s, 3H), 2.63 (s, 6H), 2.16 (s, 3H).

II-103:N4-[(4-(Dimethylamino)sulfonylamino)methylphenyl]-5-methyl-N2-(3,4,5-trimethoxyphenyl)-2,4-pyrimidinediamine

LCMS: Purity: 99%; MS (m/e): 503 (MH⁺); ¹H NMR (DMSO-d6): δ 10.19 (s,1H), 9.58 (s, 1H), 7.82 (s, 1H), 7.70 (t, 1H, J=6.2 Hz), 7.56 (d, 2H,J=8.2 Hz), 7.27 (d, 2H, J=8.5 Hz), 6.69 (s, 2H), 4.08 (d, 2H, J=6.2 Hz),3.63 (s, 3H), 3.58 (s, 6H), 2.63 (s, 6H), 2.15 (s, 3H).

II-104:N4-[(4-(Dimethylamino)sulfonylamino)methylphenyl]-5-methyl-N2-[4-(4-methyl-1-piperazinyl)phenyl]-2,4-pyrimidinediamine

LCMS: Purity: 99%; MS (m/e): 511 (MH⁺).

II-105:N4-[(4-(Dimethylamino)sulfonylamino)methylphenyl]-N2-[4-(4,4-difluoro-1-piperidinyl)phenyl]-5-methyl-2,4-pyrimidinediamine

LCMS: Purity: 99%; MS (m/e): 532 (MH⁺); ¹H NMR (DMSO-d6): δ 9.30 (s,1H), 8.87 (s, 1H), 7.78 (s, 1H), 7.68 (t, 1H, J=6.4 Hz), 7.60 (d, 2H,J=8.5 Hz), 7.37 (d, 2H, J=9.1 Hz), 7.29 (d, 2H, J=8.5 Hz), 6.88 (d, 2H,J=9.1 Hz), 4.08 (d, 2H, J=6.4 Hz), 3.26-3.22 (m, 4H), 2.64 (s, 6H), 2.10(s, 3H), 2.05-1.97 (m, 4H).

II-106:N4-[(4-(Dimethylamino)sulfonylamino)methylphenyl]-5-methyl-N2-[4-(1-methyl-4-piperidinyl)pheny]-2,4-pyrimidinediamine

LCMS: Purity: 99%; MS (m/e): 510 (MH⁺); ¹H NMR (DMSO-d6): δ 9.89 (s,1H), 9.17 (s, 1H), 7.87 (s, 1H), 7.70 (t, 1H, J=6.2 Hz), 7.57 (d, 2H,J=8.5 Hz), 7.45 (d, 2H, J=8.5 Hz), 7.30 (d, 2H, J=8.5 Hz), 7.10 (d, 2H,J=8.5 Hz), 4.10 (d, 2H, J=6.2 Hz), 3.51-3.47 (m, 2H), 3.06-3.04 (m, 2H),2.80 (s, 3H), 2.64 (s, 6H), 2.12 (2, 3H), 2.01-1.96 (m, 2H), 1.81-1.72(m, 2H).

II-107:N4-[(4-(Dimethylamino)sulfonylamino)methylphenyl]-5-methyl-N2-[4-(4-ethyl-1-piperazinyl)phenyl]-2,4-pyrimidinediamine

LCMS: Purity: 99%; MS (m/e): 525 (MH⁺).

II-108:5-chloro-N2-(3,5-Dimethyl-4-methoxyphenyl)-N4-[(4-(ethylamino)sulfonylamino)methylphenyl]-2,4-pyrimidinediamine

LCMS: Purity: 97%; MS (m/e): 492 (MH⁺); ¹H NMR (DMSO-d6): δ 9.83 (s,1H), 9.59 (s, 1H), 8.23 (s, 1H), 7.52 (d, 2H, J=8.2 Hz), 7.32 (app d,3H, J=8.2 Hz), 7.08 (s, 2H), 6.86-6.84 (m, 1H), 3.98 (s, 2H), 3.58 (s,3H), 2.84 (qt, 2H, J=7.3 Hz), 2.09 (s, 6H), 1.03 (t, 3H, J=7.3 Hz).

II-109:5-Chloro-4-[(4-(ethylamino)sulfonylamino)methylphenyl]-N2-(3,4-dimethoxy-5-methylphenyl)-2,4-pyrimidinediamine

LCMS: Purity: 97%; MS (m/e): 508 (MH⁺); ¹H NMR (DMSO-d6): δ 9.61 (s,1H), 9.35 (s, 1H), 8.18 (s, 1H), 7.55 (d, 2H, J=8.2 Hz), 7.30-7.29 (m,1H), 7.27 (d, 2H, J=8.2 Hz), 6.94 (s, 2H), 6.88-6.87 (m, 1H), 3.97 (s,2H), 3.61 (s, 3H), 3.56 (s, 3H), 2.85 (qt, 2H, J=7.3 Hz), 2.06 (s, 3H),1.03 (t, 3H, J=7.3 Hz).

II-110:5-Chloro-N2-(3-chloro-4-methoxy-5-methylphenyl)-N4-[(4-(ethylamino)sulfonylamino)methylphenyl]-2,4-pyrimidinediamine

LCMS: Purity: 97%; MS (m/e): 512 (MH⁺); ¹H NMR (DMSO-d6): δ 9.53 (s,1H), 9.11 (s, 1H), 8.17 (s, 1H), 7.54-7.52 (app d, 3H, J=8.2 Hz),7.31-7.29 (m, 4H), 6.88-6.87 (m, 1H), 3.97 (s, 2H), 3.66 (s, 3H), 2.85(qt, 2H, J=7.3 Hz), 2.12 (s, 3H), 1.04 (t, 3H, J=7.3 Hz).

II-111:5-Chloro-N2-[3,5-dichloro-4-methoxyphenyl]-N4-[(4-(ethylamino)sulfonylamino)methylphenyl]-2,4-pyrimidinediamine

LCMS: Purity: 96%; MS (m/e): 532 (MH⁺); ¹H NMR (DMSO-d6): δ 9.67 (s,1H), 9.09 (s, 1H), 8.19 (s, 1H), 7.68 (s, 2H), 7.51 9d, 2H, J=8.5 Hz),7.33 (d, 2H, J=8.2 Hz), 7.30-7.29 (m, 1H), 6.88-6.87 (m, 1H), 3.97 (s,2H), 3.72 (s, 3H), 2.85 (qt, 2H, J=7.3 Hz), 1.04 (t, 3H, J=7.3 Hz).

II-112:5-Chloro-N4-[(4-(ethylamino)sulfonylamino)methylphenyl]-N2-(3,4,5-trimethoxyphenyl)-2,4-pyrimidinediamine

LCMS: Purity: 99%; MS (m/e): 524 (MH⁺); ¹H NMR (DMSO-d6): δ 9.13 (s,1H), 8.76 (s, 1H), 8.12 (s, 1H), 7.59 (d, 1H, J=8.5 Hz), 7.29 (t, 1H,J=6.4 Hz), 7.24 (d, 2H, J=8.5 Hz), 6.96 (s, 2H), 6.86 (t, 1H, J=5.8 Hz),3.96 (d, 2H, J=6.4 Hz), 3.56 (s, 3H), 3.53 (s, 6H), 2.85 (d qt, 2H,J=5.8 and 7.0 Hz), 1.04 (t, 3H, J=7.0 Hz).

II-113:5-Chloro-N2-(3-chloro-4,5-dimethoxyphenyl)-N4-[(4-(ethylamino)sulfonylamino)methylphenyl]-2,4-pyrimidinediamine

LCMS: Purity: 99%; MS (m/e): 528 (MH⁺); ¹H NMR (DMSO-d6): δ 9.66 (s,1H), 9.23 (s, 1H), 8.20 (s, 1h), 7.53 (d, 2H, J=7.9 Hz), 7.35 (s, 1H),7.30 (d, 2H, J=8.5 Hz), 7.12 (s, 1H), 6.88-6.87 (m, 1H), 3.97 (s, 2H),3.65 (s, 3H), 3.60 (s, 3H), 2.85 (qt, 2H, J=7.0 Hz), 1.03 (t, 3H, J=7.0Hz).

II-114:5-Chloro-N4-[(4-(ethylamino)sulfonylamino)methylphenyl]-N2-[4-(4-methyl-1-piperazinyl)phenyl]-2,4-pyrimidinediamine

LCMS: Purity: 99%; MS (m/e): 532 (MH⁺); ¹H NMR (DMSO-d6): δ 9.07 (s,1H), 8.74 (s, 1H), 8.05 (s, 1H), 7.60 (d, 2H, J=8.5 Hz), 7.43 9d, 2H,J=8.2 Hz), 7.32 (t, 1H, J=6.7 Hz), 7.28 (d, 2H, J=8.5 Hz), 6.85 (t, 1H,J=5.6 Hz), 6.79 (d, 2H, J=8.8 Hz), 3.98 (d, 2H, J=6.7 Hz), 3.10 (m, 4H),2.87 (d qt, 2H, J=5.6 and 7.8 Hz), 2.70 (m, 4H), 2.40 (s, 3H), 1.04 (t,3H, J=7.3 Hz).

II-115:5-chloro-N4-[(4-(ethylamino)sulfonylamino)methylphenyl]-N2-[4-(1-methyl-4-piperidinyl)pheny]-2,4-pyrimidinediamine

LCMS: Purity: 99%; MS (m/e): 531 (MH⁺); ¹H NMR (DMSO-d6): δ 9.22 (s,1H), 8.78 (s, 1H0, 8.09 (s, 1H0, 7.60 (d, 2H, J=8.2 Hz), 7.51 (d, 2H,J=8.5 Hz), 7.34-7.27 (m, 3H), 7.04 (d, 2H, J=8.8 Hz), 6.86 (t, 1H, J=5.6Hz), 3.99 (s, 2H), 3.12 (m, 2H), 2.86 (d qt, 2H, J=5.6 and 7.8 Hz),2.40-2.38 (m, 1H), 1.81-1.63 (m, 4H), 1.04 (t, 3H, J=7.3 Hz).

II-116:N2-(3,5-Dimethyl-4-methoxyphenyl)-N4-[(4-(ethylamino)sulfonylamino)methylphenyl]-5-methyl-2,4-pyrimidinediamine

LCMS: Purity: 99%; MS (m/e): 471 (MH⁺).

II-117:N2-(3,4-Dimethoxy-5-methylphenyl)-N4-[(4-(ethylamino)sulfonylamino)methylphenyl]-5-methyl-2,4-pyrimidinediamine

LCMS: Purity: 99%; MS (m/e): 489 (MH⁺).

II-118:N2-(3-Chloro-4-methoxy-5-methylphenyl)-N4-[(4-(ethylamino)sulfonylamino)methylphenyl]-5-methyl-2,4-pyrimidinediamine

LCMS: Purity: 99%; MS (m/e): 492 (MH⁺).

II-119:N2-[3,5-Dichloro-4-methoxyphenyl]-N4-[(4-(ethylamino)sulfonylamino)methylphenyl]-5-methyl-2,4-pyrimidinediamine

LCMS: Purity: 99%; MS (m/e): 512 (MH⁺).

II-120:N4-[(4-(Ethylamino)sulfonylamino)methylphenyl]-5-methyl-N2-(3,4,5-trimethoxyphenyl)-2,4-pyrimidinediamine

LCMS: Purity: 96%; MS (m/e): 503 (MH⁺).

II-121:N2-(3-Chloro-4,5-dimethoxyphenyl)-N4-[(4-(ethylamino)sulfonylamino)methylphenyl]-5-methyl-2,4-pyrimidinediamine

LCMS: Purity: 99%; MS (m/e): 508 (MH⁺).

II-122:N4-[(4-(Ethylamino)sulfonylamino)methylphenyl]-5-methyl-N2-[4-(4-methyl-1-piperazinyl)phenyl]-2,4-pyrimidinediamine

LCMS: Purity: 99%; MS (m/e): 511 (MH⁺).

II-123:N2-[4-(4,4-Difluoro-1-piperidinyl)phenyl]-N4-[(4-(ethylamino)sulfonylamino)methylphenyl]-5-methyl-2,4-pyrimidinediamine

LCMS: Purity: 99%; MS (m/e): 532 (MH⁺).

II-124:N4-[(4-(Ethylamino)sulfonylamino)methylphenyl]-5-methyl-N2-[4-(1-methyl-4-piperidinyl)pheny]-2,4-pyrimidinediamine

LCMS: Purity: 99%; MS (m/e): 510 (MH⁺).

II-125:N4-[(4-(ethylamino)sulfonylamino)methylphenyl]-N2-[4-(4-ethyl-1-piperazinyl)phenyl]-5-methyl-2,4-pyrimidinediamine

LCMS: Purity: 99%; MS (m/e): 525 (MH⁺).

II-126:N4-[4-(N-Cyclopropylsulfonylamino)methylphenyl]-N2-(3,5-dimethyl-4-methoxyphenyl)-5-trifluoromethyl-2,4-pyrimidinediamine

LCMS: Purity: 99%; MS (m/e): 522 (MH⁺); ¹H NMR (DMSO-d6): δ 9.79 (s,1H), 8.99 (s, 1H), 8.37 9s, 1H), 7.64 (t, 1H, J=5.8 Hz), 7.42 (app d,2H, J=8.5 Hz), 7.33 9d, 2H, J=8.5 Hz), 7.08 (s, 2H), 4.17 (d, 2H, J=5.8Hz), 3.56 (s, 3H), 2.04 (s, 6H), 0.89-0.86 (m, 4H).

II-127:N4-[4-(N-Cyclopropylsulfonylamino)methylphenyl]-N2-[4-(4-methyl-1-piperazinyl)phenyl]-5-trifluoromethyl-2,4-pyrimidinediamine

LCMS: Purity: 99%; MS (m/e): 562 (MH⁺); ¹H NMR (DMSO-d6): δ 9.46 9s,1H), 8.59 (s, 1H), 8.28 (s, 1H), 7.66 (t, 1H, J=6.4 Hz), 7.42-7.31 (m,6H), 6.72 (d, 1H, J=8.5 Hz), 4.19 (d, 2H, J=6.4 Hz), 3.09-3.07 (m, 4H),2.68-2.66 (m, 4H), 2.43 9s, 3H), 0.91-0.87 (m, 4H).

II-128:N4-[4-(N-Cyclopropylsulfonylamino)methylphenyl]-N2-[3-methyl-4-(4-methyl-1-piperazinyl)phenyl]-5-trifluoromethyl-2,4-pyrimidinediamine

LCMS: Purity: 99%; MS (m/e): 576 (MH⁺); ¹H NMR (DMSO-d6): δ 8.87 (s,1H), 8.25 (s, 1H), 8.22 (s, 1H), 7.58 (t, 1H, J=6.4 Hz), 7.46-7.41 (m,2H), 7.14 (d, 2H, J=8.2 Hz), 6.79 (s, 1H), 6.73 (d, 1H, J=2.6 and 8.5Hz), 4.01 (d, 2H, J=6.4 Hz), 3.30-3.29 (m, 4H), 2.97-2.95 (m, 4H), 2.58(s, 3H), 2.08 (s, 3H), 0.88-0.85 (m, 4H).

II-129:5-Chloro-N2-(3,5-dimethyl-4-methoxyphenyl)-N4-[(3-(ethylamino)sulfonylamino)methylphenyl]-2,4-pyrimidinediamine

LCMS: Purity: 97%; MS (m/e): 492 (MH⁺); ¹H NMR (DMSO-d6): δ9.78 (s, 1H),9.59 (s, 1H), 8.23 (s, 1H), 7.54 (d, 1H, J=8.2 Hz), 7.45 (s, 1H),7.34-7.29 (m, 2H), 7.18 (d, 1H, J=8.2 Hz), 7.09 (s, 2H), 6.92-6.72 (m,1H), 3.97 (s, 2H), 3.57 (s, 3H), 2.81 (qt, 2H, J=7.3 Hz), 2.07 (s, 6H),1.02 (t, 3H, J=7.3 Hz).

II-130:5-Chloro-N2-(3,5-dimethyl-4-ethoxyphenyl)-N4-[(3-(ethylamino)sulfonylamino)methylphenyl]-2,4-pyrimidinediamine

LCMS: Purity: 99%; MS (m/e): 506 (MH⁺); ¹H NMR (DMSO-d6): δ 9.86 (s,1H), 9.66 (s, 1H), 8.25 (s, 1H), 7.53 (d, 1H, J=8.2 Hz), 7.44 (s, 1H),7.34-7.29 (m, 2H), 7.18 (d, 1H, J=8.2 Hz), 7.07 (s, 2H), 3.97 (s, 2H),3.72 (qt, 2H, J=7.0 Hz), 2.81 (qt, 2H, J=7.3 Hz), 2.06 (s, 3H), 1.29 (t,2H, J=7.0 Hz), 1.02 (t, 3H, J=7.3 Hz).

II-131:5-Chloro-N4-[(3-(ethylamino)sulfonylamino)methylphenyl]-N2-[4-(4-methyl-1-piperazinyl)phenyl]-2,4-pyrimidinediamine

LCMS: Purity: 99%; MS (m/e): 532 (MH⁺); ¹H NMR (DMSO-d6): δ 8.99 (s,1H), 8.73 (s, 1H), 8.06 (s, 1H), 7.59-7.57 (m, 2H), 7.42 (d, 2H, J=8.8Hz), 7.31-7.26 9m, 2H), 7.09 (d, 1H, J=8.2 Hz), 6.81-6.75 (m, 3H), 3.99(d, 2H, J=6.2 Hz), 3.01-3.00 (m, 4H), 2.86-2.77 (m, 2H), 2.44-2.41 (m,4H), 2.20 (s, 3H), 1.00 (t, 3H, J=7.3 Hz).

II-132:5-Chloro-N4-[(3-(ethylamino)sulfonylamino)methylphenyl]-N2-[3-methyl-4-(4-methyl-1-piperazinyl)phenyl]-2,4-pyrimidinediamine

LCMS: Purity: 97%; MS (m/e): 546 (MH⁺); ¹H NMR (DMSO-d6): δ 8.55 9s,1H0, 8.34 (s, 1H), 7.97 (s, 1H), 7.58-7.55 9m, 2H), 7.23 (t, 1H, J=5.4Hz), 7.17-7.07 (m, 2H), 6.97 (m, 1H), 6.79-6.72 (m, 2H), 3.91 (d, 2H,J=6.3 Hz), 3.19-3.17 (m, 4H), 2.86-2.77 (m, 6H), 2.11 (s, 3H), 2.86 (t,3H, J=J=7.3 Hz), 1.00 (t, 3H, J=7.3 Hz).

II-133:N2-(3,5-Dimethyl-4-methoxyphenyl)-N4-[(3-(ethylamino)sulfonylamino)methylphenyl]-5-methyl-2,4-pyrimidinediamine

LCMS: Purity: 99%; MS (m/e): 471 (MH⁺); ¹H NMR (DMSO-d6): δ 8.65 (s,1H), 8.25 (s, 1H), 7.84 (s, 1H), 7.71 (d, 1H, J=8.2 Hz), 7.54 (s, 1H),7.30-7.22 (m, 4H), 7.01 (d, 1H, J=7.6 Hz), 6.81 (t, 1H, J=5.4 Hz), 3.96(d, 1H, J=6.4 Hz), 3.77 (qt, 2H, J=7.0 Hz), 2.87-2.78 (m, 2H), 2.14 (s,3H), 2.08 (s, 3H), 1.30 (t, 3H, J=6.7 Hz), 1.01 (t, 3H, J=7.3 Hz).

II-134:N2-(3,5-Dimethyl-4-ethoxyphenyl)-N4-[(3-(ethylamino)sulfonylamino)methylphenyl]-5-methyl-2,4-pyrimidinediamine

LCMS: Purity: 99%; MS (m/e): 485 (MH⁺); ¹H NMR (DMSO-d6): δ 10.08 (s,1H0, 9.72 (s, 1h0, 7.84 (s, 1H), 7.54 (d, 1H, J=7.0 Hz), 7.41-7.29 (m,3H), 7.21 (d, 1H, J=8.2 Hz), 7.01 (s, 2H), 6.84 (t, 1H, J=5.8 Hz), 3.96(d, 1H, J=6.4 Hz), 3.77 (qt, 2H, J=7.0 Hz), 2.87-2.78 (m, 2H), 2.14 (s,3H), 2.08 (s, 3H), 1.30 (t, 3H, J=6.7 Hz), 1.01 (t, 3H, J=7.3 Hz).

II-135:N4-[(3-(Ethylamino)sulfonylamino)methylphenyl]-5-methyl-N2-[4-(4-methyl-1-piperazinyl)phenyl]-2,4-pyrimidinediamine

LCMS: Purity: 99%; MS (m/e): 511 (MH⁺); ¹H NMR (DMSO-d6): δ 8.62 (s,1H0, 8.21 (s, 1H), 7.82 (s, 1H), 7.66-7.64 (m, 2H), 7.48 (d, 2H, J=9.1Hz), 7.32-7.22 (m, 2H), 7.01 (d, 1H, J=7.3 Hz), 6.83-6.75 (m, 3H), 3.99(d, 2H, J=6.4 Hz), 3.00-2.99 (m, 4H), 2.87-2.78 (m, 2H), 2.44-2.41 (m,4H), 2.20 (s, 3H), 2.07 (s, 3H), 1.01 (t, 3H, J=7.3 Hz).

II-136:N4-[3-((Ethylamino)sulfonylamino)methylphenyl]-5-methyl-N2-[3-methyl-4-(4-methyl-1-piperazinyl)phenyl]-2,4-pyrimidinediamine

LCMS: Purity: 99%; MS (m/e): 525 (MH⁺); ¹H NMR (DMSO-d6): δ 8.06 (s,1H), 7.84 (s, 1H), 7.72 (s, 1H), 7.64-7.61 (m, 2H), 7.26-7.18 (m, 2H),7.07 (t, 1H, J=8.2 Hz), 6.90 (d, 1H, J=8.2 Hz), 6.79-6.68 (m, 3H), 3.91(d, 2H, J=6.2 Hz), 3.06-3.59 (m, 4H), 2.86-2.77 (m, 2H), 2.46-2.42 (m,4H), 2.20 (s, 3H), 2.11 (s, 3H), 2.04 (s, 3H), 1.01 (t, 3H, J=7.3 Hz).

II-137:N2-(3,5-Dimethyl-4-methoxyphenyl)-N4-[(3-(ethylamino)sulfonylamino)methylphenyl]-5-fluoro-2,4-pyrimidinediamine

LCMS: Purity: 97%; MS (m/e): 475 (MH⁺); ¹H NMR (DMSO-d6): δ 10.35 (s,1H), 9.95 9s, 1H0, 8.24 (d, 1H, J=4.7 Hz), 7.68 (d, 1H, J=8.2 Hz), 7.52(s, 1H), 7.34-7.27 (m, 2H), 7.16 (d, 1H, J=7.6 Hz), 7.11 (s, 2H),6.84-6.82 (m, 1H), 3.98 (s, 1H), 3.60 (s, 3H), 2.82 (qt, 2H, J=7.3 Hz),2.12 (s, 6H), 1.00 (t, 3H, J=7.3 Hz).

II-138:N4-[3-((Ethylamino)sulfonylamino)methylphenyl]-5-fluoro-N2-[4-(4-methyl-1-piperazinyl)phenyl]-2,4-pyrimidinediamine

LCMS: Purity: 99%; MS (m/e): 515 (MH⁺); ¹H NMR (DMSO-d6): δ 9.17 (s,1H), 8.13 (s, 1H), 7.91 (d, 1H, J=4.8 Hz), 7.66-7.64 (m, 2H), 7.47 (d,2H, J=9.1 Hz), 7.31-7.21 (m, 1H), 7.00 (d, 1H, J=7.3 Hz), 6.83-6.75 (m,3H), 3.98 (d, 2H, J=6.4 Hz), 3.00-2.99 (m, 4H), 2.87-2.78 (m, 2H),2.43-2.40 (m, 4H), 2.20 (s, 3H), 2.07 (s, 3H), 1.01 (t, 3H, J=7.3 Hz).

II-139:N4-[3-((Ethylamino)sulfonylamino)methylphenyl]-5-fluoro-N2-[3-methyl-4-(4-methyl-1-piperazinyl)phenyl]-2,4-pyrimidinediamine

LCMS: Purity: 99%; MS (m/e): 529 (MH⁺); ¹H NMR (DMSO-d6): δ 9.16 (s,1H), 8.13 (s, 1H), 7.92 (d, 1H, J=4.1 Hz), 7.65-7.62 9m, 2H), 7.25 (t,1H, J=6.4 Hz), 7.17-7.06 (m, 2H), 6.94 (d, 1H, J=8.2 Hz), 6.80-6.71 (m,3H), 3.91 (d, 2H, J=6.4 Hz), 3.09-3.06 (m, 4H), 2.87-2.78 (m, 2H),2.45-2.42 (m, 4H), 2.20 (s, 3H), 2.11 (s, 3H), 1.01 (t, 3H, J=7.3 Hz).

II-140:5-Chloro-N4-[4-[N-(Cyclopropylsulfonyl)-N′-((3-ethoxycarbonyl)propion-1-yl)amino]methylphenyl]-N2-(3,5-dimethyl-4-methoxyphenyl)-2,4-pyrimidinediamine

LCMS: Purity: 99%; MS (m/e): 617 (MH⁺); ¹H NMR (DMSO-d6): δ 9.10 (s,1H), 8.75 (s, 1H), 8.09 (s, 1H), 7.66 (d, 2H, J=8.5 Hz), 7.24 (d, 2H,J=8.5 Hz), 7.19 (s, 2H), 4.89 (s, 2H), 4.01 (qt, 2H, J=7.0 Hz), 3.56 (s,3H), 3.20-3.19 (m, 1H), 2.92 (t, 2H, J=5.8 Hz), 2.54 (t, 2H, J=5.8 Hz),2.08 (s, 6H), 1.15-1.06 (m, 7H).

II-141:5-Chloro-N4-[4-[N-cyclopropylsulfonyl)-N′-(3-(4-morpholine)propion-1-yl)amino]methylphenyl]-N2-(3,5-dimethyl-4-methoxyphenyl)-2,4-pyrimidinediamine

LCMS: Purity: 96%; MS (m/e): 630 (MH⁺); ¹H NMR (DMSO-d6): δ 9.10 (s,1H), 8.76 (s, 1H), 8.09 (s, 1H), 7.66 (d, 2H, J=8.2 Hz), 7.23 (d, 2H,J=8.2 Hz), 7.18 (s, 2H), 4.90 (s, 2H), 4.01 (qt, 2H, J=7.0 Hz), 3.56 (s,3H), 3.49-3.47 (m, 4H), 3.26-3.24 (m, 1H), 2.80 (t, 2H, J=6.4 Hz), 2.54(t, 2H, J=5.8 Hz), 2.28-2.76 (m, 4H), 2.08 (s, 6H), 1.09-1.08 (m, 4H).

II-142:5-Chloro-N2-(3,5-dimethyl-4-methoxyphenyl)-N4-[2-methyl-4-(ethylaminosulfonylamino)methylphenyl]-2,4-pyrimidinediamine

LCMS: Purity: 99%; MS (m/e): 506 (MH⁺); ¹H NMR (DMSO-d6): δ 8.96 (s,1H), 8.57 (s, 1H), 8.02 (s, 1H), 7.32-7.17 (m, 4H), 7.03 (s, 2H), 6.88(t, 1H, J=5.4 Hz), 3.98 (d, 1H, J=6.4 Hz), 3.51 (s, 1H), 2.87 (d qt, 2H,J=7.0 and 7.3 Hz), 2.15 (s, 3H), 1.96 (s, 6H), 1.06 (t, 3H, J=7.3 Hz).

II-143:5-Chloro-N2-(3,5-dimethyl-4-ethoxyphenyl)-N4-[2-methyl-4-(ethylaminosulfonylamino)methylphenyl]-2,4-pyrimidinediamine

LCMS: Purity: 99%; MS (m/e): 520 (MH⁺); ¹H NMR (DMSO-d6): δ 8.94 (s,1H), 8.56 (s, 1H), 8.01 (s, 1H), 7.32-7.17 (m, 4H), 7.03 (s, 2H), 6.88(t, 1H, J=5.4 Hz), 3.97 (d, 2H, J=6.4 Hz), 3.64 (qt, 2H, J=7.0 Hz), 2.87(d qt, 2H, J=7.0 and 7.3 Hz), 2.15 (s, 3H), 1.96 (s, 6H), 1.25 9t, 2H,J=7.0 Hz), 1.06 (t, 2H, J=7.0 Hz).

II-144:5-Chloro-N4-[2-methyl-4-(ethylaminosulfonylamino)methylphenyl]-N2-[4-(4-methyl-1-piperazinyl)phenyl]-2,4-pyrimidinediamine

LCMS: Purity: 99%; MS (m/e): 546 (MH⁺); ¹H NMR (DMSO-d6): δ 8.91 (s,1H), 7.98 (s, 1H), 7.22-7.17 (m, 6H), 6.61 (d, 2H, J=8.8 Hz), 4.00 (s,1h), 2.97-2.95 (m, 4H), 2.87 (qt, 2H, J=7.0 Hz), 2.41-2.39 (m, 4H), 2.18(s, 3H), 2.14 (s, 3H), 1.05 (t, 3H, J=7.0 Hz).

II-145:5-Chloro-N4-[2-methyl-4-(ethylaminosulfonylamino)methylphenyl]-N2-[3-methyl-4-(4-methyl-1-piperazinyl)phenyl]-2,4-pyrimidinediamine

LCMS: Purity: 99%; MS (m/e): 560 (MH⁺); ¹H NMR (DMSO-d6): δ 8.27 (s,1H), 8.11 (s, 2H), 7.89 (s, 1H), 7.33-7.28 (m, 2H), 7.16 (s, 1H), 7.09(d, 2H, J=8.5 Hz), 6.85 (t, 1H, J=5.8 Hz), 6.71 (s, 1H), 6.61 (d, 1H,J=8.2 Hz), 3.96 (d, 2H, J=6.4 Hz), 3.16-3.15 (m, 4H), 2.90-2.83 (m, 6H),2.14 (s, 3H), 2.04 (s, 3H), 1.05 (t, 3H, J=7.3 Hz).

II-146:N4-[4-(Aminosulfonylamino)methylphenyl]-5-chloro-N2-(3,5-dimethyl-4-methoxyphenyl)-2,4-pyrimidinediamine

LCMS: Purity: 96%; MS (m/e): 463 (MH⁺); ¹H NMR (DMSO-d6): δ 9.57 (s,1H), 9.32 (s, 1H), 8.17 (s, 1H), 7.53 (d, 2H, J=8.2 Hz), 7.31 (d, 2H,J=8.5 Hz), 7.11 (s, 2H), 4.04 (s, 2H), 3.56 (s, 3H), 2.09 (s, 6H).

II-147:N4-[4-(Aminosulfonylamino)methylphenyl]-5-chloro-N2-(3,5-Dimethyl-4-ethoxyphenyl)-2,4-pyrimidinediamine

LCMS: Purity: 96%; MS (m/e): 477 (MH⁺); ¹H NMR (DMSO-d6): δ 9.80 (s,1H), 9.56 (s, 1H), 8.22 (s, 1H), 7.51 (d, 2H, J=8.2 Hz), 7.32 (d, 2H,J=8.5 Hz), 7.08 (s, 2H), 4.05 (s, 2H), 3.73 (qt, 2H, J=7.0 Hz), 2.09 (s,6H), 1.29 (t, 3H, J=7.0 Hz).

II-148:N4-[4-(Aminosulfonylamino)methylphenyl]-5-chloro-N2-[4-(4-methyl-1-piperazinyl)phenyl]-2,4-pyrimidinediamine

LCMS: Purity: 96%; MS (m/e): 504 (MH⁺).

II-149:N4-[4-(Aminosulfonylamino)methylphenyl]-5-chloro-N2-[3-methyl-4-(4-methyl-1-piperazinyl)phenyl]-2,4-pyrimidinediamine

LCMS: Purity: 97%; MS (m/e): 518 (MH⁺).

II-150:5-Chloro-N2-(3,5-dimethyl-4-methoxyphenyl)-N4-[2-methyl-4-(N-cyclopropylsulfonylamino)methylphenyl]-2,4-pyrimidinediamine

LCMS: Purity: 99%; MS (m/e): 503 (MH⁺).

II-151:5-Chloro-N2-(3,5-dimethyl-4-ethoxyphenyl)-N4-[2-methyl-4-(N-cyclopropylsulfonylamino)methylphenyl]-2,4-pyrimidinediamine

LCMS: Purity: 99%; MS (m/e): 517 (MH⁺).

II-152:5-Chloro-N4-[2-methyl-4-(N-cyclopropylsulfonylamino)methylphenyl]-N2-[4-(4-methyl-1-piperazinyl)phenyl]-2,4-pyrimidinediamine

LCMS: Purity: 99%; MS (m/e): 543 (MH⁺).

II-153:5-Chloro-N4-[2-methyl-4-(N-cyclopropylsulfonylamino)methylphenyl]-N2-[3-methyl-4-(4-methyl-1-piperazinyl)phenyl]-2,4-pyrimidinediamine

LCMS: Purity: 99%; MS (m/e): 557 (MH⁺).

II-154:5-Chloro-N4-[4-((N-cyclopropylamino)sulfonylamino)methylphenyl]-N2-(3,5-dimethyl-4-methoxyphenyl)-2,4-pyrimidinediamine

LCMS: Purity: 99%; MS (m/e): 504 (MH⁺); ¹H NMR (DMSO-d6): δ 9.07 (s,1H), 8.74 (s, 1H), 8.08 (s, 1H), 7.59 (d, 2H, J=8.5 Hz), 7.43 (t, 1H,J=5.4 Hz), 7.29-7.27 (m, 3H), 7.18 (s, 2H), 3.99 (d, 2H, J=6.7 Hz), 3.56(s, 3H), 2.31-2.30 (s, 1H), 2.08- (s, 6H), 0.53-0.50 (m, 4H).

II-155:5-Chloro-N4-[4-((N-cyclopropylamino)sulfonylamino)methylphenyl]-N2-(3,5-dimethyl-4-ethoxyphenyl)-2,4-pyrimidinediamine

LCMS: Purity: 99%; MS (m/e): 518 (MH⁺); ¹H NMR (DMSO-d6): δ 9.05 (s,1H), 8.74 (s, 1H), 8.07 (s, 1H), 7.58 (d, 2H, J=8.5 Hz), 7.42 (t, 1H,J=5.4 Hz), 7.29-7.26 (m, 3H), 7.17 9s, 2H), 3.99 (d, 2H, J=6.7 Hz), 3.74(qt, 2H, J=7.3 Hz), 2.31-2.30 (m, 1H), 2.07 (s, 6H), 1.28 (t, 3H, J=7.3Hz), 0.53-0.50 (m, 4H).

II-156:5-Chloro-N4-[4-((N-cyclopropylamino)sulfonylamino)methylphenyl]-N2-(3,5-dimethyl-4-(1-methyl)ethoxyphenyl)-2,4-pyrimidinediamine

LCMS: Purity: 99%; MS (m/e): 532 (MH⁺); ¹H NMR (DMSO-d6): δ 9.05 (s,1H), 8.72 (s, 1H), 8.07 (s, 1H0, 7.59 (d, 1H, J=8.5 Hz), 7.43 (t, 1H,J=5.4 Hz), 7.29-7.26 (m, 3H), 7.17 (s, 2H), 4.05-3.97 (m, 3H), 2.31-2.29(m, 1H), 2.07 (s, 6H), 1.19-1.17 (d, 6H, J=6.0 Hz), 0.53-0.49 (m, 4H).

II-157:5-Chloro-N4-[4-((N-cyclopropylamino)sulfonylamino)methylphenyl]-N2-(3,5-dimethyl-4-propoxyphenyl)-2,4-pyrimidinediamine

LCMS: Purity: 99%; MS (m/e): 532 (MH⁺); ¹H NMR (DMSO-d6): δ 9.06 (s,1H), 8.73 (s, 1H), 8.07 (s, 1H), 7.59 (d, 2H, J=8.5 Hz), 7.42 (t, 1H,J=5.4 Hz), 7.29-7.27 (m, 3H), 7.18 (s, 2H), 3.99 (d, 2H, J=6.7 Hz), 3.60(t, 2H, J=6.6 Hz), 2.32-2.31 (m, 1H), 2.08 (s, 6H), 1.69 (q, 2H, J=6.6Hz), 1.00 (t, 3H, J=6.7 Hz), 0.53-0.51 (m, 4H).

II-158:5-Chloro-N4-[4-((N-cyclopropylamino)sulfonylamino)methylphenyl]-N2-(3,4-dimethoxy-5-methylphenyl)-2,4-pyrimidinediamine

LCMS: Purity: 99%; MS (m/e): 520 (MH⁺); ¹H NMR (DMSO-d6): δ 9.09 (s,1H), 8.76 (s, 1H), 8.09 (s, 1H), 7.59 (d, 2H, J=8.5 Hz), 7.42 (t, 1H,J=5.4 Hz), 7.29-7.27 (m, 3H), 7.18 (s, 2H), 3.99 (d, 2H, J=6.7 Hz), 3.59(s, 3H), 3.55 (s, 3H), 2.32-2.30 (m, 1H), 2.05 (s, 6H), 0.53-0.50 (m,4H).

II-159:N4-[4-(N-Cyclopropylsulfonylamino)methylphenyl]-N2-[3,4-dimethyl-4-(2-(4-morpholinyl)ethoxy)phenyl]-5-methyl-2,4-pyrimidinediamine

LCMS: Purity: 99%; MS (m/e): 567 (MH⁺); ¹H NMR (DMSO-d6): δ 9.14 (s,1H), 8.61 (s, 1H), 7.84 (s, 1H), 7.63-7.56 (m, 3H), 7.29 (d, 2H, J=8.5Hz), 7.21 (s, 2H), 4.15 (d, 2H, J=6.1 Hz), 3.96 (m, 2H), 3.80 (m, 4H),3.19-3.17 (m, 6H), 3.19-3.17 (m, 6H), 2.14 (s, 6H), 2.09 (s, 3H),0.90-0.87 (m, 4H).

II-160:5-Chloro-N4-[4-(N-cyclopropylsulfonylamino)methylphenyl]-N2-[3,4-dimethyl-4-(2-(4-morpholinyl)ethoxy)phenyl]-2,4-pyrimidinediamine

LCMS: Purity: 97%; MS (m/e): 588 (MH⁺); ¹H NMR (DMSO-d6): δ 9.04 (s,1H), 8.71 (s, 1H), 8.08 (s, 1H), 7.62-7.55 (m, 3H), 7.29 (d, 2H, J=8.5Hz), 7.18 (s, 2H), 4.16 (d, 2H, J=6.5 Hz), 3.78-3.76 (m, 2H), 3.58-3.56(m, 4H), 2.67-2.64 (m, 2H), 2.10 (s, 6H), 0.89-0.87 (m, 4H).

II-161:N2-[3,4-Dimethyl-4-(2-(4-morpholinyl)ethoxy)phenyl]-5-methyl-N4-[2-methyl-4-(N-cyclopropylsulfonylamino)methylphenyl]-2,4-pyrimidinediamine

LCMS: Purity: 99%; MS (m/e): 581 (MH⁺).

II-162:N4-[4-((N-Cyclopropylamino)sulfonylamino)methylphenyl]-N2-(3,5-dimethyl-4-methoxyphenyl)-5-methyl-2,4-pyrimidinediamine

LCMS: Purity: 99%; MS (m/e): 483 (MH⁺); ¹H NMR (DMSO-d6): δ 8.66 (s,1H), 8.17 (s, 1H), 7.83 (s, 1H), 7.64 (d, 2H, J=8.2 Hz), 7.38 (t, 1H,J=6.3 Hz), 7.27 (s, 2H), 7.24 (s, 2H), 3.98 (d, 2H, J=6.3 Hz), 3.57 (s,3H), 2.31-2.29 (m, 1H), 2.09 (s, 6H), 2.07 (s, 3H), 0.53-0.51 (m, 4H).

II-163:N4-[4-((N-Cyclopropylamino)sulfonylamino)methylphenyl]-N2-(3,5-dimethyl-4-ethoxyphenyl)-5-methyl-2,4-pyrimidinediamine

LCMS: Purity: 99%; MS (m/e): 497 (MH⁺); ¹H NMR (DMSO-d6): δ 8.69 (s,1H), 8.18 (s, 1H), 7.82 (s, 1H), 7.64 (d, 2H, J=8.2 Hz), 7.38 (t, 1H,J=6.3 Hz), 7.26 (s, 2H), 7.23 (s, 2H), 3.98 (d, 2H, J=6.3 Hz), 3.72 (qt,2H, J=7.2 Hz), 2.31-2.30 (m, 1H), 2.09 (s, 6H), 2.07 (s, 3H), 1.29 (t,3H, J=7.2 Hz), 0.53-0.51 (m, 4H).

II-164:N4-[4-((N-Cyclopropylamino)sulfonylamino)methylphenyl]-N2-[3,5-dimethyl-4-(1-methyl)ethoxyphenyl]-5-methyl-2,4-pyrimidinediamine

LCMS: Purity: 99%; MS (m/e): 511 (MH⁺); ¹H NMR (DMSO-d6): δ 8.66 (s,1H), 8.16 (s, 1H), 7.82 (s, 1H), 7.64 (d, 2H, J=8.2 Hz), 7.37 (t, 1H,J=6.3 Hz), 7.26 (s, 2H), 7.23 (s, 3H), 4.03 (sept, 1H, J=6.4 Hz), 3.98(d, 2H, J=6.3 Hz), 2.31-2.29 (m, 1H), 2.08 (s, 9H), 1.19 (d, 6H, J=6.4Hz), 0.53-0.49 (m, 4H).

II-165:N4-[4-((N-Cyclopropylamino)sulfonylamino)methylphenyl]-N2-(3,5-dimethyl-4-propoxyphenyl)-5-Methyl-2,4-pyrimidinediamine

LCMS: Purity: 99%; MS (m/e): 511 (MH⁺); ¹H NMR (DMSO-d6): δ 8.67 (s,1H), 8.17 (s, 1H), 7.82 (s, 1H), 7.64 (d, 2H, J=8.5 Hz), 7.37 (t, 1H,J=6.3 Hz), 7.26-7.24 (m, 5H), 3.98 (d, 2H, J=6.3 Hz), 3.60 (t, 2H, J=6.0Hz), 2.31-2.29 (m, 1H), 2.09 (s, 6H), 2.07 (s, 3H), 1.69 (qt, 2H, J=7.2Hz), 1.00 (t, 3H, J=7.2 Hz), 0.53-0.49 (m, 4H).

II-166:N4-[4-((N-Cyclopropylamino)sulfonylamino)methylphenyl]-N2-(3,4-dimethoxy-5-methylphenyl)-5-methyl-2,4-pyrimidinediamine

LCMS: Purity: 99%; MS (m/e): 499 (MH⁺); ¹H NMR (DMSO-d6): δ8.71 (s, 1H),8.19 (s, 1H), 7.84 (s, 1H), 7.64 (d, 2H, J=7.8 Hz), 7.38 (t, 1H, J=6.3Hz), 7.26-7.23 (m, 3H), 7.09 (d, 2H, J=8.8 Hz), 3.98 (d, 2H, J=6.9 Hz),3.59 (s, 3H), 3.57 (s, 3H), 2.31-2.29 (m, 1H), 2.07 (s, 3H), 2.06 (s,3H), 0.53-0.51 (m, 4H).

II-167:5-Chloro-N4-[4-((N-cyclopropylamino)sulfonylamino)methylphenyl]-N2-[4-(4-methyl-1-piperazinyl)phenyl]-2,4-pyrimidinediamine

LCMS: Purity: 98%; MS (m/e): 544 (MH⁺); ¹H NMR (DMSO-d6): δ 9.03 (S, 1),8.05 9s, 1H), 7.61 (d, 1H, J=2H, J=8.0 Hz), 7.42 (d, 2H, J=8.5 Hz), 7.29(d, 2H, J=8.2 Hz), 6.77 (d, 2H, J=8.8 Hz), 4.01 (s, 2H), 3.02-3.00 (m,4H), 2.42-2.04 (m, 4H), 2.33-2.31 (m, 1H), 2.19 (s, 3H), 0.55-0.52 (m,4H).

II-168:5-Chloro-N4-[4-((N-cyclopropylamino)sulfonylamino)methylphenyl]-N2-[3-methyl-4-(4-methyl-1-piperazinyl)phenyl]-2,4-pyrimidinediamine

LCMS: Purity: 98%; MS (m/e): 558 (MH⁺); ¹H NMR (DMSO-d6): δ 8.51 (s,1H), 8.40 (s, 1H), 7.96 (s, 1H), 7.59 (d, 2H, J=7.9 Hz), 7.35 (t, 1H,J=6.4 Hz), 7.26 9s, 1H), 7.14-7.12 (m, 36.78 (s, 1H), 6.74 (d, 1H, J=8.5Hz), 3.93 (d, 2H, J=6.1 Hz), 3.16 (s, 4H), 2.69 (s, 4H), 2.38 (s, 3H),2.30-2.28 (m, 1H), 2.10 (s, 3H), 0.53-0.49 (m, 4H).

II-169:5-Chloro-N4-[4-((N-cyclopropylamino)sulfonylamino)methylphenyl]-N2-[6-(4-methyl-1-piperazinyl)-3-pyridinyl]-2,4-pyrimidinediamine

LCMS: Purity: 98%; MS (m/e): 545 (MH⁺); ¹H NMR (DMSO-d6): δ 9.03 (s,1H), 8.72 (s, 1H), 9.19 (s, 1H), 7.78 (dd, 1H, J=2.3 and 8.4 Hz), 7.58(d, 2H, J=7.6 Hz), 7.42 (t, 1H, J=6.4 Hz), 7.28-7.26 (m, 3H), 6.69 (d,1H, J=8.8 Hz), 3.99 (d, 2H, J=6.4 Hz), 3.36 (m, 4H), 2.40-2.38 (m, 4H),2.31-2.29 (m, 1H), 2.20 (s, 3H), 0.54-0.50 (m, 4H).

II-170:5-Chloro-N2-[3,4-dimethyl-4-(2-(4-morpholinyl)ethoxy)phenyl]-N4-[4-((N-cyclopropylamino)sulfonylamino)methylphenyl]-2,4-pyrimidinediamine

LCMS: Purity: 98%; MS (m/e): 603 (MH⁺); ¹H NMR (DMSO-d6): δ 9.06 (s,1H), 8.72 (s, 1H), 8.08 (s, 1H), 7.59 (d, 2H, J=7.9 Hz), 7.41 (t, 1H,J=6.4 Hz), 7.29-7.27 (m, 3H), 7.18 (s, 2H), 43.99 (d, 2H, J=6.4 Hz),3.75-3.74 (m, 2H), 3.58-3.56 (m, 4H), 2.65-2.64 (m, 2H), 2.31-2.30 (m,1H), 2.10 (s, 6H), 0.54-0.51 (m, 4H).

II-171:N4-[4-((N-Cyclopropylamino)sulfonylamino)methylphenyl]-5-methyl-N2-[4-(4-methyl-1-piperazinyl)phenyl]-2,4-pyrimidinediamine

LCMS: Purity: 98%; MS (m/e): 523 (MH⁺); ¹H NMR (DMSO-d6): δ 8.76 (s,1H), 8.19 (s, 1H), 7.80 (s, 1H), 7.65 (d, 2H, J=8.2 Hz), 7.48 (d, 2H,J=8.8 Hz), 7.26 (d, 2H, J=8.5 Hz), 6.77 (d, 2H, J=8.8 Hz), 3.99 (s, 2H),3.00-2.99 (m, 4H), 2.42-2.41 (m, 4H), 2.32-2.31 (m, 1H), 2.19 (s, 3H),2.06 (s, 3H), 0.53-0.50 (m, 4H).

II-172:N4-[4-((N-Cyclopropylamino)sulfonylamino)methylphenyl]-5-methyl-N2-[3-methyl-4-(4-methyl-1-piperazinyl)phenyl]-2,4-pyrimidinediamine

LCMS: Purity: 99%; MS (m/e): 536 (MH⁺); ¹H NMR (DMSO-d6): δ 8.01 (s,1H), 7.91 (s, 1H), 7.71 (s, 1H), 7.63 (d, 2H, J=8.5 Hz), 7.33 (t, 1H,J=5.8 Hz), 7.26 (s, 1H), 7.18 (d, 1H, J=8.5 Hz), 7.10 (d, 2H, J=8.2 Hz),6.76 (s, 1H), 6.72 (d, 1H, J=8.5 Hz), 3.93 (d, 2H, J=6.2 Hz), 3.10 (m,4H), 2.29-2.25 (m, 4H), 2.10 (s, 3H), 2.03 (s, 3H), 0.53-0.49 (m, 4H).

II-173:N4-[4-((N-Cyclopropylamino)sulfonylamino)methylphenyl]-5-methyl-N2-[6-(4-methyl-1-piperazinyl)-3-pyridinyl]-2,4-pyrimidinediamine

LCMS: Purity: 99%; MS (m/e): 524 (MH⁺); ¹H NMR (DMSO-d6): δ 8.67 (s,1H), 8.25 (s, 1H), 8.18 (s, 1H), 7.86 (dd, 1H, J=2.6 and 8.8 Hz), 7.79(s, 1H), 7.63 (d, 2H, J=8.2 Hz), 7.40 (t, 1H, J=6.5 Hz), 7.27-7.23 (m,3H), 6.70 (d, 1H, J=8.8 Hz), 3.98 (d, 2H, J=6.1 Hz), 3.35-3.34 (m, 4H),2.40-2.38 (m, 4H), 2.31-2.30 (m, 1H), 2.19 (s, 3H), 2.06 (s, 3H),0.53-0.51 (m, 4H).

II-174:N2-[3,4-Dimethyl-4-(2-(4-morpholinyl)ethoxy)phenyl]-N4-[4-((N-cyclopropylamino)sulfonylamino)methylphenyl]-5-methyl-2,4-pyrimidinediamine

LCMS: Purity: 98%; MS (m/e): 582 (MH⁺); ¹H NMR (DMSO-d6): δ 8.69 (s,1H), 8.18 (s, 1H), 7.82 (s, 1H), 7.65 (d, 2H, J=8.2 Hz), 7.40 (t, 1H,J=6.4 Hz), 7.27-7.24 (m, 5H), 3.98 (d, 2H, J=6.4 Hz), 3.75 (t, 2H, J=5.9Hz), 3.58-3.55 (m, 4H), 2.64 (t, 2H, J=5.9 Hz), 2.30-2.29 (m, 1H), 2.10(s, 6H), 2.07 (s, 3H), 0.53-0.50 (m, 4H).

II-175:5-Chloro-N2-(3,5-dimethyl-4-methoxyphenyl)-N4-[2-methyl-4-((N-cyclopropylamino)sulfonylamino)methylphenyl]-2,4-pyrimidinediamine

LCMS: Purity: 98%; MS (m/e): 518 (MH⁺); ¹H NMR (DMSO-d6): δ 8.96 (s,1H), 8.58 (s, 1H), 8.01 (s, 1H), 7.45 (t, 1H, J=6.4 Hz), 7.32 (s, 1H),7.27-7.18 (m, 3H), 7.03 (s, 2H), 4.00 (d, 2H, J=6.2 Hz), 3.51 (s, 3H),2.33-2.31 (m, 1H), 2.14 (s, 3H), 1.96 (s, 6H), 0.55-0.52 (m, 4H).

II-176:5-Chloro-N2-(3,5-dimethyl-4-ethoxyphenyl)-N4-[2-methyl-4-((N-cyclopropylamino)sulfonylamino)methylphenyl]-2,4-pyrimidinediamine

LCMS: Purity: 99%; MS (m/e): 532 (MH⁺); ¹H NMR (DMSO-d6): δ8.95 (s, 1H),8.57 (s, 1H), 8.01 (s, 1H), 7.45 (t, 1H, J=6.4 Hz), 7.32 (s, 1H),7.27-7.18 (m, 3H), 7.03 (s, 2H), 4.00 (d, 2H, J=6.4 Hz), 3.64 (qt, 2H,J=6.7 Hz), 2.33-2.31 (m, 1H), 2.14 (s, 3H), 1.96 (s, 6H), 1.25 (t, 3H,J=6.7 Hz), 0.55-0.52 (m, 4H).

II-177:5-Chloro-N2-(3,5-dimethyl-4-(1-methylethoxy)phenyl)-N4-[2-methyl-4-((N-cyclopropylamino)sulfonylamino)methylphenyl]-2,4-pyrimidinediamine

LCMS: Purity: 97%; MS (m/e): 546 (MH⁺); ¹H NMR (DMSO-d6): δ 8.94 (s,1H), 8.56 (s, 1H), 8.01 (s, 1H), 7.46 (t, 1H, J=6.4 Hz), 7.32 (s, 1H),7.27-7.18 (m, 3H), 7.03 (s, 2H), 4.00-3.92 (m, 3H), 2.33-2.31 (m, 1H),2.15 (s, 3H), 1.95 (s, 6H), 1.15 (d, 6H, J=5.8 Hz), 0.55-0.52 (m, 4H).

II-178:5-Chloro-N2-(3,5-dimethyl-4-propoxyphenyl)-N4-[2-methyl-4-((N-cyclopropylamino)sulfonylamino)methylphenyl]-2,4-pyrimidinediamine

LCMS: Purity: 99%; MS (m/e): 546 (MH⁺); ¹H NMR (DMSO-d6): δ 8.95 (s,1H), 8.57 (s, 1H), 8.01 (s, 1H), 7.45 (t, 1H, J=6.4 Hz), 7.32 (s, 1H),7.27-7.18 (m, 3H), 7.03 (s, 2H), 4.01 (d, 2H, J=6.2 Hz), 3.54 (qt, 2H,J=6.4 Hz), 2.33-2.31 (m, 1H), 2.15 (s, 3H), 1.96 (s, 6H), 1.66 (m, 2H),0.97 (t, 3H, J=7.3 Hz), 0.55-0.51 (m, 4H).

II-179:5-Chloro-N2-(3,4-dimethoxy-5-methylphenyl)-N4-[2-methyl-4-((N-cyclopropylamino)sulfonylamino)methylphenyl]-2,4-pyrimidinediamine

LCMS: Purity: 98%; MS (m/e): 534 (MH⁺); ¹H NMR (DMSO-d6): δ 8.96 (s,1H), 8.57 (s, 1H), 8.01 (s, 1H), 7.46 (t, 1H, J=6.4 Hz), 7.32 (s, 1H),7.24-7.18 (m, 3H), 6.93 (app s, 2H), 4.00 (d, 2H, J=6.4 Hz), 3.53 (s,3H), 3.47 (s, 6H), 2.33-2.31 (m, 1H), 2.14 (s, 3H), 1.92 (s, 3H),0.55-0.52 (m, 4H).

II-180:5-Chloro-N4-[2-methyl-4-((N-cyclopropylamino)sulfonylamino)methylphenyl]-N2-[4-(4-methyl-1-piperazinyl)phenyl]-2,4-pyrimidinediamine

LCMS: Purity: 96%; MS (m/e): 558 (MH⁺).

II-181:5-Chloro-N4-[2-methyl-4-((N-cyclopropylamino)sulfonylamino)methylphenyl]-N2-[3-methyl-4-(4-methyl-1-piperazinyl)phenyl]-2,4-pyrimidinediamine

LCMS: Purity: 98%; MS (m/e): 572 (MH⁺).

II-182:5-Chloro-N4-[2-methyl-4-((N-cyclopropylamino)sulfonylamino)methylphenyl]-N2-[6-(4-methyl-1-piperazinyl)-3-pyridinyl]-2,4-pyrimidinediamine

LCMS: Purity: 98%; MS (m/e): 559 (MH⁺).

II-183:5-Chloro-N2-[3,4-dimethyl-4-(2-(4-morpholinyl)ethoxy)phenyl]-N4-[2-methyl-4-((N-cyclopropylamino)sulfonylamino)methylphenyl]-2,4-pyrimidinediamine

LCMS: Purity: 99%; MS (m/e): 617 (MH⁺).

II-184:N4-[4-(N-Cyclopropylsulfonylamino)methylphenyl]-5-methyl-N2-[3-methyl-4-[(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]phenyl]-2,4-pyrimidinediamine

LCMS: Purity: 99%; MS (m/e): 534 (MH⁺); ¹H NMR (DMSO-d6): δ 8.60 (s,1H), 8.15 (s, 1H), 7.80 (s, 1H), 7.69 (d, 2H, J=8.5 Hz), 7.59 (t, 1H,J=6.1 Hz), 7.30-7.23 (m, 4H), 6.63 (d, 1H, J=8.5 Hz), 3.16 (dd, 2H,J=9.3 and 19.9 Hz), 2.70 (dd, 2H, J=9.3 and 19.9 Hz), 2.44-2.40 (s, 1H),2.28 (s, 3H), 2.10 (s, 3H), 2.06 (s, 3H), 1.73 (dd, 2H, J=9.3 and 19.9Hz), 0.88-0.85 (m, 4H).

II-185:5-Chloro-N4-[4-(N-Cyclopropylsulfonylamino)methylphenyl]-N2-[3-methyl-4-[(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]phenyl]-2,4-pyrimidinediamine

LCMS: Purity: 99%; MS (m/e): 555 (MH⁺); ¹H NMR (DMSO-d6): δ 8.97 (s,1H), 8.69 (s, 1H), 8.04 (s, 1H), 7.64 (app d, 3H, J=8.2 Hz), 7.28-7.20(m, 4H), 6.62 (d, 1H, J=8.8 Hz), 4.14 (s, 2H), 3.86 (s, 1H), 3.28 (apps, 1H, 3.15 (app s, 2H), 2.68 (dd, 2H, J=9.4 and 19.9 Hz), 2.44-2.40 (s,1H), 2.25 (s, 3H), 2.25 (s, 3H), 1.70 (dd, 2H, J=9.4 and 19.9 Hz),0.88-0.85 (m, 4H).

II-187:5-Chloro-N4-[4-(N-cyclopropylsulfonylaminomethyl)phenyl]-N2-[4-(N-methylpiperidin-4-yl)phenyl]-2,4-pyrimidinediamine

LCMS: purity: 99%; MS (m/e): 528 (MH⁺)

II-188:5-Chloro-N4-[4-(N-cyclopropylsulfonylamino)methylphenyl]-N2-[4-(N-methylpiperizin-4-yl)phenyl]-2,4-pyrimidinediamine

LCMS: purity: 99%; MS (m/e): 529 (MH⁺)

II-189:5-Chloro-N4-[3-(N-cyclopropylsulfonylamino)methylphenyl]-N2-[3,4,5-trimethoxyphenyl]-2,4-pyrimidinediamine

LCMS: purity: 99%; MS (m/e): 521 (MH⁺)

II-190:5-Chloro-N4-[3-(N-cyclopropylsulfonylaminomethyl)phenyl]-N2-[4-(N-methylpiperidin-4-yl)phenyl]-2,4-pyrimidinediamine

LCMS: purity: 99%; MS (m/e): 528 (MH⁺)

II-191:5-Chloro-N4-[3-(N-cyclopropylsulfonylamino)methylphenyl]-N2-[4-(N-methylpiperizin-4-yl)phenyl]-2,4-pyrimidinediamine

LCMS: purity: 99%; MS (m/e): 529 (MH⁺)

II-192:5-Chloro-N4-[3-(N-cyclopropylsulfonylamino)methylphenyl]-N2-[3,5-dimethyl-4-methoxyphenyl]-2,4-pyrimidinediamine

LCMS: purity: 99%; MS (m/e): 489 (MH⁺)

II-193:5-Chloro-N4-[4-(N-cyclopropylsulfonylamino)methylphenyl]-N2-[4-(3-pyridinyl)phenyl]-2,4-pyrimidinediamine

LCMS: purity: 99%; MS (m/e): 508 (MH⁺)

II-194:5-Chloro-N4-[3-(N-cyclopropylsulfonylamino)methylphenyl]-N2-[4-(3-pyridinyl)phenyl]-2,4-pyrimidinediamine

LCMS: purity: 99%; MS (m/e): 508 (MH⁺)

II-196:5-Fluoro-N4-[4-(N-cyclopropylsulfonylamino)methylphenyl]-N2-[3,4-dimethoxy-5-chlorophenyl]-2,4-pyrimidinediamine

LCMS: purity: 99%; MS (m/e): 508 (MH⁺); ¹H NMR (DMSO-d6): δ 8.19 (d, 1H,J=1.9 Hz), 7.71 (d, 2H, J=8.4 Hz), 7.58 (m, 1H), 7.54 (s, 1H), 7.29 (d,2H, J=8.4 Hz), 7.21 (s, 1H), 4.15 (d, 2H, J=6 Hz), 3.61 (s, 3H), 3.57(s, 3H), 2.45 (m, 1H), 0.88 (m, 4H).

II-199:5-Chloro-N4-[4-(N-cyclopropylsulfonylamino)methylphenyl]-N2-[3,4-dimethoxy-5-methylphenyl]-2,4-pyrimidinediamine

LCMS: purity: 99%; MS (m/e): 505 (MH⁺); ¹H NMR (DMSO-d6): δ 8.19 (s,1H), 7.59 (m, 3H), 7.29 (d, 2H, J=8.4 Hz), 6.94 (s, 2H), 4.15 (d, 2H,J=6 Hz), 3.61 (s, 3H), 3.57 (s, 3H), 2.45 (m, 1H), 2.06 (s, 3H), 0.88(m, 4H).

II-200:5-Chloro-N4-[4-(N-cyclopropylsulfonylamino)methylphenyl]-N2-[3,4-dimethoxy-5-chlorophenyl]-2,4-pyrimidinediamine

LCMS: purity: 99%; MS (m/e): 525 (MH⁺); ¹H NMR (DMSO-d6): δ8.15 (s, 1H),7.63 (m, 3H), 7.43 (s, 1H), 7.32 (d, 1H, J=8.4 Hz), 7.18 (d, 1H, J=1.5Hz), 4.15 (d, 2H, J=6 Hz), 3.64 (s, 3H), 3.60 (s, 3H), 2.42 (m, 1H),0.88 (m, 4H).

II-202:5-Methyl-N4-[4-(N-cyclopropylsulfonylamino)methylphenyl]-N2-[3-methyl-4-(N-methylpiperizin-4-yl)phenyl]-2,4-pyrimidinediamine

LCMS: purity: 99%; MS (m/e): 522 (MH⁺)

II-203:5-Chloro-N4-[4-(N-cyclopropylsulfonylamino)methylphenyl]-N2-[3-methyl-4-(N-methylpiperizin-4-yl)phenyl]-2,4-pyrimidinediamine

LCMS: purity: 99%; MS (m/e): 543 (MH⁺); ¹H NMR (DMSO-d6): δ 8.55 (σ,1H), 8.44 (σ, 1H), 8.13 (s, 1H), 7.98 (s, 1H), 7.58 (m, 3H), 7.16 (m,3H), 6.79 (m, 2H), 4.09 (d, 2H, J=6.0 Hz), 3.29 (s, 4H), 3.10 (s, 4H),2.67 (s, 3H), 2.42 (m, 1H), 2.11 (s, 3H), 0.88 (m, 4H).

II-204:5-Methyl-N4-[4-(N-cyclopropylsulfonylamino)methylphenyl]-N2-[4-(N-ethylpiperizin-4-yl)phenyl]-2,4-pyrimidinediamine

LCMS: purity: 99%; MS (m/e): 522 (MH⁺)

II-205:5-Chloro-N4-[4-(N-cyclopropylsulfonylamino)methylphenyl]-N2-[4-(N-ethylpiperizin-4-yl)phenyl]-2,4-pyrimidinediamine

LCMS: purity: 99%; MS (m/e): 543 (MH⁺)

II-206:5-Methyl-N4-[4-(N-cyclopropylsulfonylamino)methylphenyl]-N2-[4-[N-(methansulfonyl)piperizin-4-ylphenyl]-2,4-pyrimidinediamine

LCMS: purity: 99%; MS (m/e): 572 (MH⁺)

II-207:5-Chloro-N4-[4-(N-cyclopropylsulfonylamino)methylphenyl]-N2-[4-[N-(methansulfonyl)piperizin-4-ylphenyl]-2,4-pyrimidinediamine

LCMS: purity: 99%; MS (m/e): 593 (MH⁺)

II-209:5-Methyl-N4-[4-(N-cyclopropylsulfonylamino)methylphenyl]-N2-[3,4-dimethoxy-5-ethoxyphenyl]-2,4-pyrimidinediamine

LCMS: purity: 99%; MS (m/e): 514 (MH⁺)

II-210:5-Chloro-N4-[4-(N-cyclopropylsulfonylamino)methylphenyl]-N2-[3,4-dimethoxy-5-ethoxyphenyl]-2,4-pyrimidinediamine

LCMS: purity: 99%; MS (m/e): 535 (MH⁺)

II-211:5-Chloro-N4-[4-(N-cyclopropylsulfonylamino)methylphenyl]-N2-[3,5-dimethyl-4-ethoxyphenyl]-2,4-pyrimidinediamine

LCMS: purity: 99%; MS (m/e): 503 (MH⁺)

II-212:5-Methyl-N4-[4-(N-cyclopropylsulfonylamino)methylphenyl]-N2-[2,4-dimethyl-5-chlorophenyl]-2,4-pyrimidinediamine

LCMS: purity: 99%; MS (m/e): 505 (MH⁺)

II-213:5-Chloro-N4-[4-(N-cyclopropylsulfonylamino)methylphenyl]-N2-[2,4-dimethyl-5-chlorophenyl]-2,4-pyrimidinediamine

LCMS: purity: 99%; MS (m/e): 525 (MH⁺)

II-214:5-Methyl-N4-[4-(N-cyclopropylsulfonylamino)methylphenyl]-N2-[3,5-dimethyl-4-ethoxyphenyl]-2,4-pyrimidinediamine

LCMS: purity: 99%; MS (m/e): 482 (MH⁺)

II-215:5-Methyl-N4-[4-(N-cyclopropylsulfonylamino)methylphenyl]-N2-[4-(N-methylpiperizin-4-yl)pyridine-3-yl]-2,4-pyrimidinediamine

LCMS: purity: 99%; MS (m/e): 509 (MH⁺)

II-216:5-Chloro-N4-[4-(N-cyclopropylsulfonylamino)methylphenyl]-N2-[4-(N-methylpiperizin-4-yl)pyridine-3-yl]-2,4-pyrimidinediamine

LCMS: purity: 99%; MS (m/e): 530 (MH⁺)

II-217:5-Chloro-N4-[4-(N-cyclopropyl-N-acetylsulfonylamino)methylphenyl]-N2-[3,4-dimethyl-5-methoxyphenyl]-2,4-pyrimidinediamine

LCMS: purity: 99%; MS (m/e): 531 (MH⁺)

II-218:5-Chloro-N4-[4-(N-cyclopropyl-N-propionylsulfonylamino)methylphenyl]-N2-[3,5-dimethyl-4-methoxyphenyl]-2,4-pyrimidinediamine

LCMS: purity: 99%; MS (m/e): 545 (MH⁺)

II-219:5-Methyl-N4-[4-(N-cyclopropylsulfonylamino)methylphenyl]-N2-[3,5-dimethyl-4-(2-propoxy)phenyl]-2,4-pyrimidinediamine

LCMS: purity: 99%; MS (m/e): 496 (MH⁺)

II-220:5-Chloro-N4-[4-(N-cyclopropylsulfonylamino)methylphenyl]-N2-[3,5-dimethyl-4-(2-propoxy)phenyl]-2,4-pyrimidinediamine

LCMS: purity: 99%; MS (m/e): 517 (MH⁺)

II-221:5-Chloro-N4-[4-(N-cyclopropylsulfonylamino)methylphenyl]-N2-[3,5-dimethyl-4-(1-propoxy)phenyl]-2,4-pyrimidinediamine

LCMS: purity: 99%; MS (m/e): 517 (MH⁺)

II-222:5-Methyl-N4-[4-(N-cyclopropylsulfonylamino)methylphenyl]-N2-[4-(1-morpholinomethyl)phenyl]-2,4-pyrimidinediamine

LCMS: purity: 99%; MS (m/e): 516 (MH⁺)

II-223:5-Chloro-N4-[4-(N-cyclopropylsulfonylamino)methylphenyl]-N2-[4-(1-morpholinomethyl)phenyl]-2,4-pyrimidinediamine

LCMS: purity: 99%; MS (m/e): 530 (MH⁺)

II-224:5-Methyl-N4-[4-(N-cyclopropylsulfonylamino)methylphenyl]-N2-[5-methyl-4-(N-methylpiperizin-4-yl)pyridin-3-yl]-2,4-pyrimidinediamine

LCMS: purity: 99%; MS (m/e): 523 (MH⁺); ¹H NMR (DMSO-d6): δ8.11 (d, 1H,J=1.8 Hz), 7.41 (m, 3H), 7.24 (m, 1H), 6.93 (d, 1H, J=8.4 Hz), 6.71 (d,2H, J=9 Hz), 3.10 (s, 8H), 2.97 (s, 3H), 2.60 (s, 3H), 1.42 (s, 6H).

II-225:5-Chloro-N4-[4-(N-cyclopropylsulfonylamino)methylphenyl]-N2-[5-methyl-4-(N-methylpiperizin-4-yl)pyridin-3-yl]-2,4-pyrimidinediamine

LCMS: purity: 99%; MS (m/e): 544 (MH⁺)

III-1:N4-[4-(Cyclopropylsulfonylaminomethyl)phenyl]-5-fluoro-N2-[1-(2-(N-morpholino)ethyl)indol-6-yl]-2,4-pyrimidinediamine

LCMS: purity: 91%; MS (m/e): 567 (MH⁺); ¹H NMR (CDCl₃): δ 7.93 (d, J=3.3Hz, 1H), 7.87-7.84 (m, 1H), 7.61 (d, J=8.4 Hz, 2H), 7.49 (d, J=8.4 Hz,1H), 7.29 (d, J=8.4 Hz, 2H), 7.18 (s, 1H), 7.04 (d, J=3.3 Hz, 1H), 6.91(dd, J=1.8 and 8.7 Hz, 1H), 6.85 (d, J=3.0 Hz, 1H), 6.43 (d, J=3.0 Hz,1H), 5.92-5.84 (m, 1H), 4.28 (d, J=5.4 Hz, 2H), 4.10 (t, J=7.2 Hz, 2H),3.63 (t, J=4.5 Hz, 4H), 2.63 (t, J=7.2 Hz, 2H), 2.41-2.36 (m, 1H), 2.33(t, J=4.5 Hz, 4H), 1.18 (dd, J=2.1 and 5.1 Hz, 2H), 0.97 (dd, J=2.1 and8.1 Hz, 2H).

III-2:N4-[4-(Cyclopropylsulfonylaminomethyl)phenyl]-5-fluoro-N2-[1-(2-(N-morpholino)ethylaminocarbonyl)indol-6-yl]-2,4-pyrimidinediamine

LCMS: purity: 97%; MS (m/e): 609 (MH⁺); ¹H NMR (CDCl₃): δ 8.49 (s, 1H),7.91 (d, J=3.6 Hz, 1H), 7.57-7.47 (m, 5H), 7.16 (d, J=8.4 Hz, 2H), 6.99(dd, J=1.8 and 8.4 Hz, 1H), 6.94 (d, J=2.4 Hz, 1H), 6.58-6.52 (m, 2H),6.50 (t, J=5.7 Hz, 1H), 4.25 (d, J=6.0 Hz, 2H), 3.42 (t, J=3.9 Hz, 4H),3.04 (q, J=5.1 Hz, 2H), 2.53-2.44 (m, 1H), 2.27-2.23 (m, 6H), 1.26-1.21(m, 2H), 1.03-0.97 (m, 2H).

III-3:N4-(4-cyclopropylsulfonylaminomethyl)phenyl-5-methyl-N2-(2-methylbenzoimidazol-5-yl)-2,4-pyrimidinediamine

LCMS: purity: 99.34%; MS (m/e): 463.87 (MH+); ¹H NMR (DMSO-d₆): δ 0.89(m, 4H), 2.10 (s, 3H), 2.43 (s, 3H), 4.15 (d, J=5.7 Hz, 2H), 7.25 (d,J=8.1 Hz, 3H), 7.33 (d, J=8.7 Hz, 1H), 7.56 (t, J=6.0 Hz, 1H), 7.74 (d,J=8.1 Hz, 2H), 7.83 (d, J=7.2 Hz, 1H), 7.84 (s, 1H), 8.16 (s, 1H), 8.78(s, 1H), 11.86 (br, 1H).

III-4:N4-(3-cyclopropylsulfonylaminomethyl)phenyl-5-methyl-N2-(2-methylbenzoimidazol-5-yl)-2,4-pyrimidinediamine

LCMS: purity: 100%; MS (m/e): 463.83 (MH+); ¹H NMR (DMSO-d₆): δ 0.86 (m,4H), 2.10 (s, 3H), 2.43 (s, 3H), 4.16 (d, 2H), 7.04 (d, 1H), 7.25 (t,3H), 7.64 (br, 1H), 7.79 (s, 1H), 7.86 (s, 1H), 8.21 (s, 1H), 8.73 (s,1H).

III-5:N4-(4-cyclopropylsulfonylaminomethyl)phenyl-5-fluoro-N2-(2-methylbenzoimidazol-5-yl)-2,4-pyrimidinediamine

LCMS: purity: 92.68%; MS (m/e): 467.82 (MH+); ¹H NMR (DMSO-d₆): δ 0.89(m, 4H), 2.43 (s, 3H), 4.13 (d, 2H), 7.25 (d, J=8.4 Hz, 2H), 7.30 (s,2H), 7.57 (br, 1H), 7.80 (m, 3H), 8.05 (s, 1H), 9.07 (s, 1H), 9.26 (s,1H), 11.92 (br, 1H).

III-6:5-chloro-N4-(4-cyclopropylsulfonylaminomethyl)phenyl-N2-(2-methylbenzoimidazol-5-yl)-2,4-pyrimidinediamine

LCMS: purity: 93.36%; MS (m/e): 484.00 (MH+); ¹H NMR (DMSO-d6): δ 0.89(m, 4H), 2.44 (s, 3H), 4.17 (d, J=6.3 Hz, 2H), 7.27 (d, J=8.4 Hz, 4H),7.61 (t, 1H), 7.69 (d, J=8.1 Hz, 3H), 8.09 (s, 1H), 8.69 (s, 1H), 9.16(s, 1H).

III-7:5-Chloro-N4-[3-(N-cyclopropylsulfonylaminomethyl)phenyl]-N2-[2-methylbenzamidazol-5-yl]-2,4-pyrimidinediamine

LCMS: purity: 99%; MS (m/e): 484 (MH⁺)

IV-1:N2-(benzoimidazol-5-yl)-N4-(4-cyclopropylsulfonylaminomethyl)phenyl-5-methyl-2,4-pyrimidinediamine

LCMS: purity: 98.31%; MS (m/e): 449.81 (MH+); ¹H NMR (DMSO-d₆): δ 0.90(m, 4H), 2.11 (s, 3H), 4.16 (d, J=6.0 Hz, 2H), 7.27 (d, J=8.4 Hz, 2H),7.39 (s, 2H), 7.70 (br, 1H), 7.73 (d, J=8.1 Hz, 2H), 7.86 (s, 1H), 8.01(d, J=11.4 Hz, 2H), 8.21 (s, 1H), 8.88 (s, 1H), 12.09 (br, 1H).

IV-2:N4-(4-cyclopropylsulfonylaminomethyl)phenyl-5-methyl-N2-(2-trifluoromethylbenzoimidazol-5-yl)-2,4-pyrimidinediamine

LCMS: purity: 96.32%; MS (m/e): 518.34 (MH+); ¹H NMR (DMSO-d₆): δ 0.85(m, 4H), 2.17 (s, 3H), 2.42 (m, 1H), 4.15 (d, J=6.3 Hz, 2H), 7.29 (d,J=8.4 Hz, 2H), 7.42 (d, J=7.5 Hz, 1H), 7.55 (d, J=8.4 Hz, 2H), 7.62 (t,J=6.3 Hz, 1H), 7.64 (m, 2H), 7.82 (s, 1H), 9.61 (s, 1H), 10.32 (s, 1H);¹⁹F NMR (282 MHz, DMSO-d₆): δ −63.56.

IV-3:N4-(4-cyclopropylsulfonylaminomethyl)phenyl-5-methyl-N2-[2-(pyridin-3-yl)benzoimidazol-5-yl]-2,4-pyrimidinediamine

LCMS: purity: 92.02%; MS (m/e): 527.16 (MH+); ¹H NMR (DMSO-d₆): δ 0.89(m, 4H), 2.12 (s, 3H), 4.16 (d, J=6.3 Hz, 2H), 7.28 (d, J=7.8 Hz, 2H),7.50 (s, 2H), 7.56 (m, 2H), 7.77 (d, J=8.1 Hz, 2H), 7.89 (s, 1H), 8.10(s, 1H), 8.22 (s, 1H), 8.43 (m, 1H), 8.61 (d, 1H), 9.02 (s, 1H), 9.27(br, 1H).

IV-4:N2-(2-tert-butylbenzoimidazol-5-yl)-N4-(4-cyclopropylsulfonylaminomethyl)phenyl-5-methyl-2,4-pyrimidinediamine

LCMS: purity: 97.51%; MS (m/e): 506.27 (MH+); ¹H NMR (DMSO-d₆): δ 0.89(m, 4H), 1.38 (s, 9H), 2.10 (s, 3H), 2.43 (m, 1H), 4.13 (d, J=6.0 Hz,2H), 7.24 (d, J=8.4 Hz, 2H), 7.34 (s, 2H), 7.55 (t, 1H), 7.76 (d, J=8.4Hz, 2H), 7.84 (s, 1H), 7.85 (d, J=8.4 Hz, 1H), 8.15 (s, 1H), 8.84 (s,1H), 11.80 (br, 1H).

IV-5:N4-(4-cyclopropylsulfonylaminomethyl)phenyl-5-methyl-N2-[2-(thien-2-yl)benzoimidazol-5-yl]-2,4-pyrimidinediamine

LCMS: purity: 99.77%; MS (m/e): 532.13 (MH+); ¹H NMR (DMSO-d₆): δ 0.89(m, 4H), 2.12 (s, 3H), 2.43 (m, 1H), 4.16 (d, J=5.7 Hz, 2H), 7.18 (d,1H), 7.28 (d, J=7.2 Hz, 2H), 7.45 (m, 2H), 7.58 (t, 1H), 7.65 (m, 1H),7.72 (m, 1H), 7.77 (d, J=8.4 Hz, 2H), 7.88 (s, 1H), 8.00 (s, 1H), 8.21(s, 1H), 8.98 (s, 1H).

IV-6:N4-(4-cyclopropylsulfonylaminomethyl)phenyl-5-methyl-N2-[2-(morpholin-4-yl)methylbenzoimidazol-5-yl]-2,4-pyrimidinediamine

LCMS: purity: 94.31%; MS (m/e): 549.03 (MH+); ¹H NMR (DMSO-d₆): δ 0.90(m, 4H), 2.10 (s, 3H), 2.44 (m, 4H), 3.59 (m, 4H), 3.76 (m, 2H), 4.14(d, J=6.0 Hz, 2H), 7.25 (d, J=7.8 Hz, 2H), 7.35 (s, 2H), 7.57 (t, J=6.3Hz, 1H), 7.76 (d, J=8.1 Hz, 2H), 7.85 (m, 2H), 8.17 (s, 1H), 8.87 (s,1H), 11.99 (br, 1H).

IV-7:N4-(4-cyclopropylsulfonylaminomethyl)phenyl-N2-(1,2-dimethylbenzoimidazol-5-yl)-5-methyl-2,4-pyrimidinediamine

LCMS: purity: 92.35%; MS (m/e): 478.09 (MH+); ¹H NMR (DMSO-d₆): δ 0.87(m, 4H), 2.09 (s, 3H), 3.66 (s, 3H), 4.16 (d, J=6.0 Hz, 2H), 7.23 (d,J=9.0 Hz, 1H), 7.26 (d, J=7.8 Hz, 2H), 7.42 (d, J=8.4 Hz, 1H), 7.60 (t,1H), 7.70 (d, J=8.4 Hz, 2H), 7.83 (s, 2H), 8.17 (s, 1H), 8.75 (s, 1H).

IV-8:N4-(4-cyclopropylsulfonylaminomethyl)phenyl-N2-[1-(2-hydroxyethyl)benzoimidazol-5-yl]-5-methyl-2,4-pyrimidinediamine

LCMS: purity: 77.37%; MS (m/e): 494.13 (MH+); ¹H NMR (DMSO-d₆): δ 0.90(m, 4H), 2.15 (s, 3H), 3.77 (m, 2H), 4.17 (d, J=5.7 Hz, 2H), 4.42 (m,2H), 7.31 (d, J=7.8 Hz, 2H), 7.57 (m, 2H), 7.66 (m, 1H), 7.73 (d, J=8.1Hz, 2H), 7.85 (s, 1H).

IV-9:N4-(3-cyclopropylsulfonylaminomethyl)phenyl-N2-[1-(2-hydroxyethyl)benzoimidazol-5-yl]-5-methyl-2,4-pyrimidinediamine

LCMS: purity: 92.50%; MS (m/e): 494.19 (MH+); ¹H NMR (DMSO-d₆): δ 0.89(m, 4H), 2.16 (s, 3H), 3.77 (m, 2H), 4.17 (d, J=6.6 Hz, 2H), 4.40 (m,2H), 7.15 (d, 1H), 7.30 (m, 2H), 7.59 (m, 2H), 7.77 (d, 2H), 7.86 (s,1H).

IV-10:N4-(3-cyclopropylsulfonylaminomethyl)phenyl-N2-(1,2-dimethylbenzoimidazol-5-yl)-5-methyl-2,4-pyrimidinediamine

LCMS: purity: 97.62%; MS (m/e): 478.18 (MH+); ¹H NMR (DMSO-d₆): δ 0.89(m, 4H), 2.16 (s, 3H), 2.74 (s, 3H), 3.87 (s, 3H), 4.13 (d, J=5.7 Hz,2H), 7.11 (d, J=8.7 Hz, 1H), 7.31 (t, J=8.7 Hz, 1H), 7.61-7.69 (m, 5H),7.91 (s, 1H).

IV-11:N4-(3-cyclopropylsulfonylaminomethyl)phenyl-5-methyl-N2-[2-(thien-2-yl)benzoimidazol-5-yl]-2,4-pyrimidinediamine

LCMS: purity: 100%; MS (m/e): 532.11 (MH+); ¹H NMR (DMSO-d₆): δ 0.84 (m,4H), 2.15 (s, 3H), 2.43 (m, 1H), 4.14 (d, 2H), 7.07 (d, J=8.1 Hz, 1H),7.20 (t, J=4.2 Hz, 1H), 7.28 (m, 2H), 7.42 (m, 1H), 7.70 (m, 3H), 7.77(m, 1H), 7.84 (s, 2H), 8.11 (s, 1H).

IV-12:N4-(3-cyclopropylsulfonylaminomethyl)phenyl-5-methyl-N2-[2-(pyridin-3-yl)benzoimidazol-5-yl]-2,4-pyrimidinediamine

LCMS: purity: 100%; MS (m/e): 527.29 (MH+); ¹H NMR (DMSO-d₆): δ 0.83 (m,4H), 2.15 (s, 3H), 2.44 (m, 1H), 4.15 (d, J=6.6 Hz, 2H), 7.08 (d, J=6.9Hz, 1H), 7.29 (t, J=7.8 Hz, 1H), 7.37 (d, J=7.8 Hz, 1H), 7.50 (d, J=7.2Hz, 1H), 7.56 (dd, J=4.8, 8.1 Hz, 1H), 7.64 (m, 2H), 7.71 (s, 1H), 7.86(s, 1H), 7.97 (s, 1H), 8.43 (d, J=7.8 Hz, 1H), 8.64 (d, J=4.8 Hz, 1H),9.29 (s, 1H).

IV-13:N2-(benzoimidazol-5-yl)-N4-(3-cyclopropylsulfonylaminomethyl)phenyl-5-methyl-2,4-pyrimidinediamine

LCMS: purity: 99.04%; MS (m/e): 449.85 (MH+); ¹H NMR (DMSO-d₆): δ 0.87(m, 4H), 2.16 (s, 3H), 4.13 (d, J=6.0 Hz, 2H), 7.11 (d, J=8.4 Hz, 1H),7.30 (t, J=7.5 Hz, 1H), 7.52 (m, 1H), 7.62 (d, J=8.7 Hz, 3H), 7.69 (t,1H), 7.88 (s, 1H), 8.01 (br, 1H), 8.96 (br, 2H), 9.79 (br, 1H).

IV-14:N4-(3-cyclopropylsulfonylaminomethyl)phenyl-5-methyl-N2-(2-trifluoromethylbenzoimidazol-5-yl)-2,4-pyrimidinediamine

LCMS: purity: 95.99%; MS (m/e): 518.00 (MH+); ¹H NMR (DMSO-d₆): δ 0.86(m, 4H), 2.15 (s, 3H), 2.43 (m, 1H), 4.14 (d, J=5.7 Hz, 2H), 7.08 (d,1H), 7.27 (t, J=7.8 Hz, 1H), 7.51 (m, 1H), 7.59 (m, 2H), 7.67 (m, 2H),7.88 (s, 1H), 8.01 (s, 1H), 8.70 (br, 1H), 9.39 (br, 1H); ¹⁹F NMR (282MHz, DMSO-d₆): δ −63.34.

IV-15:N2-(2-tert-butylbenzoimidazol-5-yl)-N4-(3-cyclopropylsulfonylaminomethyl)phenyl-5-methyl-2,4-pyrimidinediamine

LCMS: purity: 99.70%; MS (m/e): 506.55 (MH+); ¹H NMR (DMSO-d₆): δ 0.86(m, 4H), 1.48 (s, 9H), 2.16 (s, 3H), 2.43 (m, 1H), 4.13 (d, J=6.3 Hz,2H), 7.09 (d, J=8.1 Hz, 1H), 7.28 (t, J=7.8 Hz, 1H), 7.55 (s, 2H), 7.62(d, J=6.9 Hz, 3H), 7.89 (s, 1H), 7.98 (br, 1H), 9.86 (br, 1H).

IV-16:N4-(3-cyclopropylsulfonylaminomethyl)phenyl-5-methyl-N2-[2-(morpholin-4-yl)methylbenzoimidazol-5-yl]-2,4-pyrimidinediamine

LCMS: purity: 99.22%; MS (m/e): 549.05 (MH+); ¹H NMR (DMSO-d₆): δ 0.86(m, 4H), 2.11 (s, 3H), 2.44 (m, 4H), 3.60 (m, 4H), 3.66 (s, 2H), 4.15(d, J=5.1 Hz, 2H), 7.01 (d, J=7.5 Hz, 1H), 7.24 (t, J=7.8 Hz, 1H), 7.30(s, 2H), 7.66 (br, 1H), 7.77 (s, 1H), 7.86 (s, 1H), 7.90 (br, 1H), 8.23(s, 1H), 8.77 (s, 1H).

V-1:(+/−)-5-Methyl-N4-[1-(methylsulfonylamino)indan-6-yl]-N2-(3,4,5-trimethoxyphenyl)-2,4-pyrimidinediamine

LCMS: ret. time: 3.58 min.; Purity: 99%; MS (m/e): 500 (MH⁺); ¹H NMR(DMSO-d6): δ 8.68 (s, 1H), 8.34 (s, 1H), 7.86 (s, 1H), 7.65 (d, 1H,J=9.1 Hz), 7.52 (s, 1H), 7.49 (d, 1H, J=8.8 Hz), 7.12 (d, 1H, J=8.2 Hz),7.02 (s, 2H), 4.73 (qt, 1H, J=8.20 Hz), 3.56 (s, 3H), 3.51 (s, 6H), 2.93(s, 3H), 2.87-2.83 (m, 1H), 2.76-2.66 (m, 1H), 2.54-2.48 (m, 1H), 2.08(s, 3H), 1.97-1.80 (s, 1H).

V-2:(+/−)-5-Methyl-N2-[4-(1-methyl-4-piperidinyl)pheny]-N4-[1-(methylsulfonyl)aminoindan-6-yl]-2,4-pyrimidinediamine

LCMS: Purity: 99%; MS (m/e): 507 (MH⁺); ¹H NMR (DMSO-d6): δ 8.75 (s,1H), 8.31 (s, 1H), 7.83 (s, 1H), 7.71 (d, 1H, J=7.6 Hz), 7.57-7.49 (m,4H), 7.17 (d, 1H, J=8.5 Hz), 7.00 (d, 1H, J=8.2 Hz), 4.79 (qt, 1H, J=7.6Hz), 3.02-2.98 (m, 2H), 2.95 (s, 3H), 2.88-2.71 (m, 2H), 2.33 (s, 3H),2.27-2.17 (m, 2H), 2.08 (s, 3H), 1.97-1.82 (m, 1H), 1.76-1.60 (m, 4H).

V-3:(+/−)-N4-[1-(Cyclopropylsulfonylamino)indan-6-yl]-5-Methyl-N2-(3,4,5-trimethoxyphenyl))-2,4-pyrimidinediamine

LCMS: Purity: 99%; MS (m/e): 526 (MH⁺); ¹H NMR (DMSO-d6): δ 8.96 (s,1H), 8.36 (s, 1H), 7.86 (s, 1H), 7.58-7.26 (m, 2H), 7.51 (d, 1H, J=9.1Hz), 7.14 (d, 1H, J=9.1 Hz), 7.01 (s, 2H), 4.73 (qt, 1H, J=8.2 Hz), 3.57(s, 3H), 3.49 (s, 5H), 2.90-2.83 (m, 1H), 2.75-2.67 (m, 2H), 2.45-2.42(m, 1H), 1.95-1.85 (m, 1H), 0.89-0.84 (m, 4H).

V-4:(+/−)-N4-[1-(Cyclopropylsulfonylamino)indan-6-yl]-5-methyl-N2-[4-(4-methyl-1-piperazinyl)phenyl]-2,4-pyrimidinediamine

LCMS: Purity: 99%; MS (m/e): 534 (MH⁺); ¹H NMR (DMSO-d6): δ 8.56 (s,1H), 8.26 (s, 1H), 7.80 (s, 1H), 7.67 (d, 1H, J=8.2 Hz), 7.58-7.45 (m,4H), 7.15 (d, 1H, J=8.2 Hz), 6.77 (d, 2H, J=8.5 Hz), 4.79 (qt, 1H, J=7.6Hz), 3.04-3.03 (m, 4H), 2.90-2.83 (m, 1H), 2.75-2.67 (m, 1H), 2.57-2.55(m, 4H), 2.30 (s, 3H), 1.95-1.85 (m, 1H), 0.89-0.84 (m, 4H).

V-5:(+/−)-N4-[1-(Cyclopropylsulfonylamino)indan-6-yl]-5-methyl-N2-[4-(1-methyl-4-piperidinyl)pheny]-2,4-pyrimidinediamine

LCMS: Purity: 99%; MS (m/e): 533 (MH⁺); ¹H NMR (DMSO-d6) δ 8.75 (s, 1H),8.32 (s, 1H), 7.83 (s, 1H), 7.66 (d, 1H, J=8.5 Hz), 7.56-7.51 (m, 4H),7.17 (d, 1H, J=8.2 Hz), 6.99 (d, 2H, J=8.2 Hz), 4.79 (qt, 1H, J=7.9 Hz),3.03-2.99 (m, 2H), 2.90-2.83 (m, 1H), 2.80-2.70 (m, 1H), 2.56-2.53 (m,1H), 2.39-2.33 (m, 1H), 2.34 (s, 3H), 2.29-2.22 (m, 2H), 2.06 (s, 3H),1.99-1.86 (m, 1H), 1.76-1.66 (m, 2H), 0.96-0.85 (m, 4H).

V-6:(+/−)-N4-[1-(Cyclopropylsulfonylamino)indan-6-yl]-N2-[4-(4,5-dihydro-1H-imidazol-2-yl)phenyl]-5-methyl-2,4-pyrimidinediamine

LCMS: Purity: 99%; MS (m/e): 504 (MH⁺).

V-7:(+/−)-N4-[1-(Cyclopropylsulfonylamino)indan-6-yl]-N2-(3,5-dimethyl-4-methoxyphenyl)-5-methyl-2,4-pyrimidinediamine

LCMS: Purity: 99%; MS (m/e): 494 (MH⁺); ¹H NMR (DMSO-d6): δ 8.06 (s,1H), 8.30 (s, 1H), 7.81 (s, 1H), 7.64 (d, 1H, J=8.5 Hz), 7.54 (s, 1H,J=8.5 Hz), 7.51 (s, 1H), 7.23 (s, 2H), 7.15 (d, 1H, J=8.2 Hz), 4.75 (qt,1H, J=7.9 Hz), 3.55 (s, 3H), 2.91-2.77 (m, 1H), 2.74-2.69 (m, 1H),2.51-2.50 (m, 2H), 2.05 (s, 3H), 1.97-1.91 (m, 1H), 0.96-0.89 (m, 4H).

V-8:(+/−)-N4-[1-(Cyclopropylsulfonylamino)indan-6-yl]-N2-(3,5-dichloro-4-methoxyphenyl)-5-methyl-2,4-pyrimidinediamine

LCMS: Purity: 99%; MS (m/e): 535 (MH⁺); ¹H NMR (DMSO-d6): δ 9.17 (s,1H), 8.47 (s, 1H), 7.88 (s, 1H), 7.74 (s, 2H), 7.54 (d, 2H, J=9.0 Hz),7.45 (s, 1H), 7.20 (d, 1H, J=9.2 Hz), 4.80 (app qt, 1H, J=7.9 Hz), 3.71(s, 3H), 2.92-2.77 (m, 1H), 2.74-2.69 (m, 1H), 2.57-2.56 (s, 1H), 2.09(s, 3H), 1.95-1.85 (m, 1H), 0.96-0.81 (m, 4H).

V-9:(1R)-5-Methyl-N4-[(1-(methylsulfonylamino)indan-6-yl]-N2-(3,4,5-trimethoxyphenyl)-2,4-pyrimidinediamine

LCMS: Purity: 99%; MS (m/e): 500 (MH⁺); ¹H NMR (DMSO-d6): δ 8.68 (s,1H), 8.34 (s, 1H), 7.85 (s, 1H), 7.64 (d, 1H, J=8.2 Hz), 7.51-7.47 (m,2H), 7.11 (d, 1H, J=8.5 Hz), 7.02 (s, 2H), 4.80 (qt, 1H, J=7.9 Hz), 4.78(qt, 1H, J=7.9 Hz), 3.57 (s, 3H), 3.49 (s, 6H), 2.91-2.78 (m, 1H),2.75-2.70 (m, 1H), 2.57-2.52 (m, 1H).

V-10:(1R)—N2-(3,5-dimethyl-4-methoxyphenyl)-5-methyl-N4-[(1-(methylsulfonylamino)indan-6-yl]-2,4-pyrimidinediamine

LCMS: Purity: 99%; MS (m/e): 468 (MH⁺); ¹H NMR (DMSO-d6): 8.60 (s, 1H),8.29 (s, 1H), 7.81 (s, 1H), 7.71 (dd, 1H, J=2.0 and 8.8 Hz), 7.51 (d,1H, J=8.8 Hz), 7.44 (s, 1H), 7.23 (s, 2H), 7.14 (d, 1H, J=8.2 Hz), 4.76(q, 1H, J=8.5 Hz), 3.55 (s, 3H), 2.96 (s, 3H), 2.91-2.83 (m, 1H),2.76-2.66 (m, 1H), 2.57-2.52 (m, 1H), 2.06 (s, 9H), 1.97-1.84 (m, 1H).

V-11:(1R)-5-Methyl-N2-[4-(1-methyl-4-piperidinyl)pheny]-N4-[1-(methylsulfonyl)aminoindan-6-yl]-2,4-pyrimidinediamine

LCMS: Purity: 99%; MS (m/e): 507 (MH⁺); ¹H NMR (DMSO-d6): δ 8.76 (s,1H), 8.31 (s, 1H), 7.83 (s, 1H), 7.71 (dd, 1H, J=2.2 and 8.2 Hz),7.57-7.49 (m, 4H), 7.17 (d, 1H, J=8.2 Hz), 7.01 (d, 2H, J=8.8 Hz), 4.79(qt, 1H, J=7.9 Hz), 3.10 (m, 1H), 2.95 (s, 3H), 2.89-2.68 (m, 2H),2.56-2.51 (m, 1H), 2.41-2.38 (m, 1H), 2.32 (s, 3H), 2.25-2.18 (m, 2H),2.08 (s, 3H), 1.97-1.88 (m, 1H), 1.75-1.63 (m, 4H).

V-12:(1R)-5-Methyl-N4-[1-(methylsulfonyl)aminoindan-6-yl]-N2-[4-(3-pyridinyl)phenyl]-2,4-pyrimidinediamine

LCMS: Purity: 99%; MS (m/e): 487 (MH⁺); ¹H NMR (DMSO-d6): δ 9.06 (s,1H), 8.84 (s, 1H), 8.44-8.46 (m, 1H), 8.38 (s, 1H), 8.00-7.97 (m, 1H),7.89 (s, 1H), 7.81 (d, 2H, J=8.8 Hz), 7.72 (d, 1H, J=8.2 Hz), 7.53-7.51(m, 4H), 7.44-7.40 (m, 1H), 7.23 (d, 1H, J=8.0 Hz), 4.81 (qt, 1H, J=7.9Hz), 2.97 (s, 3H), 2.89-2.68 (m, 2H), 2.56-2.50 (m, 1H), 2.10 (s, 3H),1.92-1.84 (m, 1H).

V-13:(1R)—N2-(3,5-Dichloro-4-methoxyphenyl))-5-methyl-N4-[1-(methylsulfonyl)aminoindan-6-yl]-2,4-pyrimidinediamine

LCMS: Purity: 99%; MS (m/e): 509 (MH⁺); ¹H NMR (DMSO-d6): δ 9.17 (s,1H), 8.45 (s, 1H), 7.88 (s, 1H), 7.75 (s, 2H), 7.59 (d, 1H, J=8.5 Hz),7.49 (d, 1H, J=8.8 Hz), 7.39 (s, 1H), 7.20 (d, 1H, J=8.2 Hz), 4.79 (qt,1H, J=8.2 Hz), 3.71 (s, 3H), 2.96 (s, 3H), 2.86-2.83 (m, 1H), 2.74-2.69(m, 1H), 2.54-2.51 (m, 1H), 2.09 (s, 3H), 1.91-1.84 (s, 1H).

V-14:(1R)-5-Methyl-N2-[4-(4-methyl-1-piperazinyl)phenyl]-N4-[1-(methylsulfonyl)aminoindan-6-yl]-2,4-pyrimidinediamine

LCMS: Purity: 99%; MS (m/e): 508 (MH⁺); ¹H NMR (DMSO-d6): δ: 8.55 (s,1H), 8.25 (s, 1H), 7.79 (s, 1H), 7.72 (d, 1H, J=8.2 Hz), 7.52-7.45 (m,4H), 7.15 (d, 1H, J=8.2 Hz), 6.76 (d, 2H, J=9.1 Hz), 4.78 (qt, 1H, J=7.9Hz), 3.01 (m, 4H), 2.96 (s, 3H), 2.90-2.71 (m, 2H), 2.53-2.51 (m, 1H),2.23 (s, 3H), 2.06 (s, 3H), 1.92-1.84 (s, 1H).

VI-1:5-Chloro-N2-[4-(4-methyl-1-piperazinyl)phenyl]-N4-[1,2,3,4-tetrahydro-2-(ethylsulfonyl)-5-isoquinolinyl]-2,4-pyrimidinediamine

LCMS: Purity: 99%; MS (m/e): 543 (MH⁺); ¹H NMR (DMSO-d6): δ 9.00 (s,1H), 8.62 (s, 1H), 8.03 (s, 1H), 7.27-7.15 (m, 5H), 6.65 (d, 2H, J=8.5Hz), 4.46 (s, 2H), 3.39 (t, 2H, J=5.6 Hz), 3.11-2.97 (m, 10H), 2.71-2.69(m, 2H), 2.56 (s, 3H), 1.11 (t, 3H).

VI-2:5-Chloro-N2-[3-methyl-4-(methyl-1-piperazinyl)phenyl]-N4-[1,2,3,4-tetrahydro-2-(ethylsulfonyl)-5-isoquinolinyl]-2,4-pyrimidinediamine

LCMS: Purity: 99%; MS (m/e): 557 (MH⁺); ¹H NMR (DMSO-d6): δ 8.36 (s,1H), 8.15 (s, 1H), 7.92 (s, 1H), 7.26 (d, 1H, J=7.6 Hz), 7.18-7.01 (m,3H), 6.70 (s, 1H), 6.61 (d, 1H, J=8.8 Hz), 4.39 (s, 2H), 3.39 (t, 2H,J=5.6 Hz), 3.10-3.03 (m, 7H), 2.70-2.65 (m, 5H), 2.03 (s, 3H), 1.17 (t,3H, J=7.3 Hz).

VI-3:5-Chloro-N2-[6-(4-methyl-1-piperazinyl)-3-pyridinyl]-N4-[1,2,3,4-tetrahydro-2-(ethylsulfonyl)-5-isoquinolinyl]-2,4-pyrimidinediamine

LCMS: Purity: 99%; MS (m/e): 544 (MH⁺).

VI-4:5-Chloro-N2-(3,5-dimethyl-4-methoxyphenyl)N4-[1,2,3,4-tetrahydro-2-(ethylsulfonyl)-5-isoquinolinyl]-2,4-pyrimidinediamine

LCMS: Purity: 97%; MS (m/e): 503 (MH⁺); ¹H NMR (DMSO-d6): δ 9.00 (s,1H), 8.62 (s, 1H), 8.03 (s, 1H), 7.29-7.22 (m, 2H), 7.16 (d, 1H, J=7.3Hz), 7.01 (s, 2H), 4.43 (s, 2H), 3.49 (s, 3H), 3.39 (t, 2H, J=5.6 Hz),2.99 (qt, 2H, J=6.6 Hz), 2.71-2.69 (m, 2H), 1.94 (s, 6H), 1.08 (t, 3H,J=7.3 Hz).

VI-5:5-Chloro-N4-[1,2,3,4-tetrahydro-2-(ethylsulfonyl)-5-isoquinolinyl]-N2-(3,4,5-trimethoxyphenyl)-2,4-pyrimidinediamine

LCMS: Purity: 98%; MS (m/e): 535 (MH⁺); ¹H NMR (DMSO-d6): δ 9.03 (s,1H), 8.59 (s, 1H), 8.09 (s, 1H), 7.22-7.21 (m, 2H), 7.12-7.11 (m, 1H),6.85 (s, 2H), 4.41 (s, 2H), 3.51 (s, 2H), 3.40 (app s, 6H), 3.03 (qt,2H, J=7.3 Hz), 2.72 (t, 2H, J=5.9 Hz), 1.08 (t, 3H, J=7.3 Hz).

VII-1:5-Chloro-N4-[3,4-dihydro-1,1-dioxide-2H-1,2-benzothiazin-7-yl]-N2-[3,5-dimethyl-4-methoxyphenyl]-2,4-pyrimidinediamine

LCMS: purity: 99%; MS (m/e): 460 (MH⁺); ¹H NMR (DMSO-d6): δ8.12 (s, 1H),8.04 (d, 1H, J=8.4 Hz), 7.74 (s, 1H), 7.43 (m, 1H), 7.26 (d, 1H, J=8.7Hz), 7.16 (s, 2H), 3.54 (m, 5H), 2.88 (m, 2H), 2.07 (s, 6H).

VII-2:5-Chloro-N4-[3,4-dihydro-1,1-dioxide-2H-1,2-benzothiazin-7-yl]-N2-[4-(N-methylpiperizin-4-yl)phenyl]-2,4-pyrimidinediamine

LCMS: purity: 99%; MS (m/e): 501 (MH⁺); ¹H NMR (DMSO-d6): δ8.11 (d, 1H,J=7.5 Hz), 8.02 (m, 1H), 7.84 (s, 1H), 7.42 (m, 2H), 7.28 (d, 1H, J=8.4Hz), 6.71 (d, 2H, J=7.4 Hz), 6.84 (d, J=8.7 Hz), 3.55 (m, 2H), 3.16 (bs,3H), 2.88 (bs, 5H), 2.53 (s, 3H).

VII-3:5-Chloro-N4-[3,4-dihydro-1,1-dioxide-2H-1,2-benzothiazin-7-yl]-N2-[4-(N-methylpiperizin-4-yl)pyridine-3-yl]-2,4-pyrimidinediamine

LCMS: purity: 99%; MS (m/e): 502 (MH⁺); ¹H NMR (DMSO-d6): δ8.22 (s, 1H),8.11 (d, 1H, J=1.8 Hz), 7.98 (s, 1H), 7.77 (m, 2H), 7.41 (m, 1H), 6.93(d, 1H, J=8.4 Hz), 6.81 (d, 1H, J=9 Hz), 3.54 (m, 7H), 2.87 (m, 5H),2.52 (s, 3H).

VII-4:5-Chloro-N4-[3,4-dihydro-1,1-dioxide-2H-1,2-benzothiazin-7-yl]-N2-[5-methyl-4-(N-methylpiperizin-4-yl)pyridine-3-yl]-2,4-pyrimidinediamine

LCMS: purity: 99%; MS (m/e): 516 (MH⁺); ¹H NMR (DMSO-d6): δ8.18 (s, 1H),8.12 (d, 1H, J=4.2 Hz), 7.95 (m, 1H), 7.78 (m, 2H), 7.43 (m, 1H), 7.25(d, J=8.2 Hz), 3.55 (m, 4H), 3.07 (m, 5H), 2.87 (m, 6H), 2.54 (m, 3H),2.09 (s, 3H).

VII-5:5-Chloro-N4-[3,4-dihydro-1,1-dioxide-2H-1,2-benzothiazin-7-yl]-N2-[4-(N-methylpiperizin-4-yl)phenyl]-2,4-pyrimidinediamine

LCMS: purity: 99%; MS (m/e): 480 (MH⁺); ¹H NMR (DMSO-d6): δ 8.11 (s,1H), 7.83 (m, 3H), 7.68 (m, 1H), 7.48 (m, 1H), 7.28 (d, 1H, J=6 Hz),7.00 (m, 2H), 4.34 (bs, 2H), 3.56 (m, 4H), 3.08 (m, 4H), 2.86 (m, 5H),2.13 (s, 3H).

VII-6:5-Methyl-N4-[3,4-dihydro-1,1-dioxide-2H-1,2-benzothiazin-7-yl]-N2-[5-methyl-4-(N-methylpiperizin-4-yl)pyridine-3-yl]-2,4-pyrimidinediamine

LCMS: purity: 99%; MS (m/e): 481 (MH⁺); ¹H NMR (DMSO-d6): δ7.82 (m, 3H),7.45 (m, 3H), 7.27 (m, 3H), 7.00 (m, 3H), 3.97 (m, 4H), 3.54 (m, 4H),3.13 (m, 6H), 2.86 (m, 5H), 2.13 (s, 3H).

VII-7:5-Methyl-N4-[3,4-dihydro-1,1-dioxide-2H-1,2-benzothiazin-7-yl]-N2-[5-methyl-4-(N-methylpiperizin-4-yl)pyridine-3-yl]-2,4-pyrimidinediamine

LCMS: purity: 99%; MS (m/e): 495 (MH⁺); ¹H NMR (DMSO-d6): δ8.10 (s, 1H),7.94 (s, 1H), 7.82 (d, 1H, J=8.6 Hz), 7.74 (s, 1H), 7.65 (s, 1H), 7.48(m, 1H), 7.25 (d, 1H, J=8.1 Hz), 3.49 (m, 5H), 3.14 (m, 3H), 2.98 (m,4H), 2.13 (m, 6H).

VII-8:5-Methyl-N4-[3,4-dihydro-1,1-dioxide-2H-1,2-benzothiazin-7-yl]-N2-[3,4,5-trimethylphenyl]-2,4-pyrimidinediamine

LCMS: purity: 99%; MS (m/e): 472 (MH⁺); ¹H NMR (DMSO-d6): δ8.18 (d, 1H,J=9.8 Hz), 8.11 (m, 1H), 7.91 (s, 1H), 7.39 (m, 1H), 7.20 (d, 1H, J=8.7Hz), 7.01 (s, 2H), 3.74 (s, 2H), 3.62 (s, 1H), 3.56 (m, 9H), 3.31 (m,2H), 2.84 (m, 2H), 2.08 (s, 3H).

VII-9:5-Chloro-N4-[3,4-dihydro-1,1-dioxide-2H-1,2-benzothiazin-7-yl]-N2-[3,4,5-trimethylphenyl]-2,4-pyrimidinediamine

LCMS: purity: 99%; MS (m/e): 492 (MH⁺); ¹H NMR (DMSO-d6): δ8.12 (d, 1H,J=9.8 Hz), 7.98 (m, 1H), 7.76 (s, 1H), 7.43 (m, 1H), 7.24 (d, 1H, J=8.7Hz), 7.04 (s, 1H), 6.93 (s, 2H), 3.74 (s, 2H), 3.62 (s, 1H), 3.54 (m,9H), 2.85 (m, 2H).

VII-10:5-Methyl-N4-[3,4-dihydro-1,1-dioxide-2H-1,2-benzothiazin-7-yl]-N2-[3,5-dimethyl-4-methoxyphenyl]-2,4-pyrimidinediamine

LCMS: purity: 99%; MS (m/e): 440 (MH⁺); ¹H NMR (DMSO-d6): δ8.76 (s, 1H),8.49 (s, 1H), 8.20 (d, 1H, J=8.7 Hz), 8.14 (s, 1H), 7.87 (s, 1H), 7.72(s, 1H), 7.41 (m, 1H), 7.211 (m, 3H), 3.53 (m, 5H), 2.85 (m, 2H), 2.08(m, 9H).

VIII-1: N4,N6-Di(3-aminosulfonylphenyl)-5-methyl-N2-(2,2,4-trimethyl-3-oxo-2H-benz[1,4]oxazin-6-yl)-2,4,6-pyrimidinetriamine

LCMS: ret. time: 7.06 min.; Purity: 99%; MS (m/e): 639 (MH⁺); ¹H NMR(DMSO-d6): δ 8.62 (s, 1H), 8.46 (s, 1H), 7.94 (s, 4H), 7.39-7.31 (m,9H), 7.22 (d, 1H, J=8.8 Hz), 6.75 (d, 1H, J=8.8 Hz), 2.88 (s, 3H), 2.12(s, 3H), 1.34 (s, 6H).

VIII-2:N2-cyclopentyl-N4-(4-cyclopropylsulfonylaminomethyl)phenyl-5-fluoro-2,4-pyrimidinediamine

LCMS: purity: 95.92%; MS (m/e): 406.57 (MH+); ¹H NMR (DMSO-d₆): δ 0.89(m, 4H), 1.48 (m, 4H), 1.65 (m, 2H), 1.86 (m, 2H), 2.42 (m, 1H), 4.01(q, J=6.9 Hz, 1H), 4.12 (s, 2H), 6.70 (d, J=6.9 Hz, 1H), 7.24 (d, J=8.4Hz, 2H), 7.55 (br, 1H), 7.80 (d, J=8.7 Hz, 2H), 7.88 (d, J=3.9 Hz, 1H),9.06 (br, 1H); ¹⁹F NMR (282 MHz, DMSO-d₆): δ −168.62.

VIII-3:(+/−)-N2-(1,2-Dimethylbenzimidazol-5-yl)-N4-[1-(methylsulfonylamino)indan-6-yl]-5-methyl-2,4-pyrimidinediamine

LCMS: ret. time: 2.25 min.; Purity: 99%; MS (m/e): 478 (MH⁺); ¹H NMR(DMSO-d6): δ 8.73 (s, 1H), 8.54 (d, 1H, J=8.5 Hz), 8.23 (s, 1H), 8.01(s, 1H), 7.82 (s, 1H), 7.59 (s, 1H), 7.44 (d, 1H, J=8.0 Hz), 7.24-7.13(m, 1H), 4.87 (app qt, 1H, 8.8 and 7.6 Hz), 3.64 (s, 3H), 2.90 (s, 3H),2.85-2.74 (m, 3H), 2.564-2.47 (m, 1H), 2.08 (s, 3H), 2.02-1.97 (m, 1H).

VIII-4:5-Fluoro-N4-[(1-methylsulfonyl)indolin-5-yl]-N2-(2-trifluoromethylbenzimidazol-5-yl)-2,4-pyrimidinediamine

LCMS (m/z): 508 (MH⁺); ¹H NMR (DMSO d₆, 300 MHz): δ 10.05 (s, 1H), 9.98(s, 1H), 8.21 (d, 1H, J=4.5 Hz), 8.00 (s, 1H), 7.67 (s, 1H), 7.64 (d,1H, J=8.4 Hz), 7.46 (t, 2H, J=9.0 Hz), 7.18 (d, 1H, J=9.0 Hz), 3.91 (t,2H, J=8.4 Hz), 2.99 (t, 2H, J=8.1 Hz), 2.94 (s, 3H).

VIII-5:(N4-[(1-methylsulfonyl)indolin-5-yl]-5-fluoro-N2-[3-methyl-4-(4-methylpiperazin-1-yl)phenyl]-2,4-pyrimidinediamine

LCMS (m/z): 512 (MH⁺); ¹H NMR (DMSO d₆, 300 MHz): δ 9.24 (s, 1H), 8.95(s, 1H), 8.01 (d, 1H, J=3.9 Hz), 7.64 (s, 1H), 7.59 (d, 1H, J=8.7 Hz),7.37 (m, 2H), 7.18 (d, 1H, J=9.0 Hz), 6.89 (d, 1H, J=9.0 Hz), 3.94 (t,2H, J=8.1 Hz), 3.09 (t, 2H, J=8.4 Hz), 2.96 (s, 3H), 2.83 (s, 4H), 2.67(s, 4H), 2.39 (s, 3H), 2.16 (s, 3H).

VIII-6:5-Fluoro-N4-[(1-methylsulfonyl)indolin-5-yl]-N2-(2-methylbenzimidazol-5-yl)-2,4-pyrimidinediamine

LCMS (m/z): 454 (MH⁺); ¹H NMR (DMSO d₆, 300 MHz): δ 9.24 (s, 1H), 9.01(s, 1H), 8.03 (d, 1H, J=3.6 Hz), 7.81 (s, 1H), 7.75 (s, 1H), 7.57 (d,1H, J=8.7 Hz), 7.25 (m, 2H), 7.16 (d, 1H, J=8.7 Hz), 3.92 (t, 2H, J=8.1Hz), 3.03 (t, 2H, J=7.8 Hz), 2.49 (s, 3H), 2.44 (s, 3H).

VIII-7:N4-[(N-cyclopropylsulfonyl)-1,2,3,4-tetrahydroisoquinolin-6-yl]-N2-(3,5-dimethyl)phenyl-5-methyl-2,4-pyrimidinediamine

LCMS: purity: 98.71%; MS (m/e): 464.56 (MH+); ¹H NMR (DMSO-d₆): δ 0.99(m, 4H), 2.09 (s, 3H), 2.12 (s, 6H), 2.64 (t, J=6.3 Hz, 1H), 2.86 (t,J=5.7 Hz, 2H), 3.49 (t, J=5.7 Hz, 2H), 4.38 (s, 2H), 6.47 (s, 1H), 7.11(d, J=8.1 Hz, 1H), 7.23 (s, 2H), 7.42 (s, 1H), 7.56 (d, J=8.4 Hz, 1H),7.85 (s, 1H), 8.23 (s, 1H), 8.80 (s, 1H);

VIII-8:5-Amino-N4-(3-aminosulfonylphenyl)-N2-(indazoline-6-yl)-2,4-pyrimidinediamine

LCMS: ret. time: 2.76 min.; Purity: 99%; MS (m/e): 397 (MH⁺); ¹H NMR(DMSO-d6): δ 8.60 (s, 1H), 8.53 (s, 1H), 8.29-8.25 (m, 1H), 8.16-8.15(m, 1H), 8.00 (s, 1H), 7.85 (s, 1H), 7.69 (s, 1H), 7.48-7.41 (m, 4H),7.37-7.35 (m, 3H).

VIII-9:N4-[(N-cyclopropylsulfonyl)-1,2,3,4-tetrahydroisoquinolin-6-yl]-N2-(3,5-dimethyl-4-methoxy)phenyl-5-methyl-2,4-pyrimidinediamine

MS (m/e): 494.20 (MH+); ¹H NMR (DMSO-d₆): δ 0.98 (m, 4H), 2.09 (s, 9H),2.64 (m, 1H), 2.83 (t, 2H), 3.48 (t, J=6.0 Hz, 2H), 3.58 (s, 3H), 4.39(s, 2H), 7.12 (d, J=8.1 Hz, 1H), 7.17 (s, 2H), 7.39 (s, 1H), 7.50 (d,J=7.5 Hz, 1H), 7.81 (s, 1H), 8.55 (br, 1H), 8.97 (br, 1H); LCMS: purity:98.39%;

VIII-10:N4-[(N-ethylsulfonyl)-1,2,3,4-tetrahydroisoquinolin-6-yl]-N2-(3,5-dimethyl-4-methoxy)phenyl-5-fluoro-2,4-pyrimidinediamine

LCMS: purity: 83.39%; MS (m/e): 486.09 (MH+); ¹H NMR (DMSO-d6): δ 1.21(t, J=7.2 Hz, 3H), 2.11 (s, 6H), 2.81 (t, 2H), 3.12 (q, J=7.5 Hz, 2H),3.47 (t, 2H), 3.58 (s, 3H), 4.37 (s, 2H), 7.09 (d, J=7.8 Hz, 1H), 7.22(s, 2H), 7.50 (s, 1H), 7.58 (d, 1H), 8.03 (s, 1H), 8.92 (s, 1H), 9.22(s, 1H);

VIII-11:5-Methyl-N4-[4-(N-cyclopropylsulfonylamino)methylphenyl]-N2-[5-cyclopropylpyrazol-3-yl)-2,4-pyrimidinediamine

LCMS: purity: 99%; MS (m/e): 440 (MH+)

VIII-12:5-Chloro-N4-[4-(N-cyclopropylsulfonylamino)methylphenyl]-N2-[5-cyclopropylpyrazol-3-yl)-2,4-pyrimidinediamine

LCMS: purity: 99%; MS (m/e): 460 (MH+); ¹H NMR (DMSO-d6): δ 8.80 (s,1H), 8.04 (s, 1H), 7.69 (m, 3H), 7.28 (d, 1H, J=9.3 Hz), 6.15 (s, 1H),4.14 (d, 2H), J=6.0 Hz), 1.85 (m, 4H), 0.93 (m, 4H) 0.63 (m, 1H);

B. Example 2 Assay for Ramos B-Cell Line Stimulated with IL-4

B-cells stimulated with cytokine Interleukin-4 (IL-4) activate theJAK/Stat pathway through phosphorylation of the JAK family kinases,JAK-1 and JAK-3, which in turn phosphorylate and activate thetranscription factor Stat-6. One of the genes upregulated by activatedStat-6 is the low affinity IgE receptor, CD23. To study the effect ofinhibitors on the JAK family kinases, human Ramos B cells are stimulatedwith human IL-4.

The Ramos B-cell line was acquired from ATCC (ATCC Catalog No.CRL-1596). The cells were cultured in RPMI 1640 (Cellgro, MediaTech,Inc., Herndon, Va., Cat No. 10-040-CM) with 10% fetal bovine serum(FBS), heat inactivated (JRH Biosciences, Inc, Lenexa, Kans., Cat No.12106-500M) according to ATCC propagation protocol. Cells weremaintained at a density of 3.5×10⁵. The day before the experiment, RamosB-cells were diluted to 3.5×10⁵ cells/mL to ensure that they were in alogarithmic growth phase.

Cells were spun down and suspended in RPMI with 5% serum. 5×10⁴ cellswere used per point in a 96-well tissue culture plate. Cells werepre-incubated with compound or DMSO (Sigma-Aldrich, St. Louis, Mo., CatNo. D2650) vehicle control for 1 hour in a 37° C. incubator.

Cells were then stimulated with IL-4 (Peprotech Inc., Rocky Hill, N.J.,Cat No. 200-04) for a final concentration of 50 units/mL for 20-24hours. Cells were then spun down and stained with anti-CD23-PE (BDPharmingen, San Diego, Calif., Cat No. 555711) and analyzed by FACS.Detection was performed using a BD LSR I System Flow Cytometer,purchased from Becton Dickinson Biosciences of San Jose, Calif. The IC₅₀calculated based on the results of this assay are provided in Table XI.

C. Example 3 Primary Human T-cell Proliferation Assay Stimulated withIL-2

Primary human T-cells derived from peripheral blood and pre-activatedthrough stimulation of the T-cell receptor and CD28, proliferate invitro in response to the cytokine Interleukin-2 (IL-2). Thisproliferative response is dependent on the activation of JAK-1 and JAK-3tyrosine kinases, which phosphorylate and activate the transcriptionfactor Stat-5.

Human primary T cells were prepared as follows. Whole blood was obtainedfrom a healthy volunteer, mixed 1:1 with PBS, layered on to FicollHypaque (Amersham Pharmacia Biotech, Piscataway, N.J., Catalog#17-1440-03) in 2:1 blood/PBS:ficoll ratio and centrifuged for 30 min at4° C. at 1750 rpm. The lymphocytes at the serum: ficoll interface wererecovered and washed twice with 5 volumes of PBS. The cells wereresuspended in Yssel's medium (Gemini Bio-products, Woodland, Calif.,Catalog #400-103) containing 40 U/mL recombinant IL2 (R and D Systems,Minneapolis, Minn., Catalog #202-IL (20 μg)) and seeded into a flaskpre-coated with 1 μg/mL anti-CD3 (BD Pharmingen, San Diego, Calif.,Catalog #555336) and 5 μg/mL anti-CD28 (Immunotech, Beckman Coulter ofBrea Calif., Catalog #IM1376). The primary T-cells were stimulated for3-4 days, then transferred to a fresh flask and maintained in RPMI with10% FBS and 40 U/mL IL-2.

Primary T-cells were washed twice with PBS to remove the IL-2 andresuspended in Yssel's medium at 2×106 cells/mL. 50 μL of cellsuspension containing 80 U/mL IL-2 was added to each well of a flatbottom 96 well black plate. For the unstimulated control, IL-2 wasomitted from the last column on the plate. Compounds were seriallydiluted in dimethyl sulfoxide (DMSO, 99.7% pure, cell culture tested,Sigma-Aldrich, St. Louis, Mo., Catalog No. D2650) from 5 mM in 3-folddilutions, and then diluted 1:250 in Yssel's medium. 50 μL of 2×compound was added per well in duplicate and the cells were allowed toproliferate for 72 hours at 37° C.

Proliferation was measured using CellTiter-Glo® Luminescent CellViability Assay (Promega), which determines the number of viable cellsin culture based on quantitation of the ATP present, as an indicator ofmetabolically active cells. The substrate was thawed and allowed to cometo ambient temperature. After mixing the Cell Titer-Glo reagent anddiluent together, 100 μL was added to each well. The plates were mixedon an orbital shaker for two minutes to induce lysis and incubated atambient temperature for an additional ten minutes to allow the signal toequilibrate. Detection was performed using a Wallac Victor2 1420multilabel counter purchased from Perkin Elmer, Shelton, Conn.

D. Example 4 A549 Epithelial Line Stimulated with IFNγ

A549 lung epithelial cells up-regulate ICAM-1 (CD54) surface expressionin response to a variety of different stimuli. Therefore, using ICAM-1expression as readout, compound effects on different signaling pathwayscan be assessed in the same cell type. IFNγ up-regulates ICAM-1 throughactivation of the JAK/Stat pathway. In this example, the up-regulationof ICAM-1 by IFNγ was assessed.

The A549 lung epithelial carcinoma cell line originated from theAmerican Type Culture Collection. Routine culturing was with F12K media(Mediatech Inc., Lenexa, Kans., Cat. No. 10-025-CV) with 10% fetalbovine serum, 100 I.U. penicillin and 100 ng/mL streptomycin (completeF12k media). Cells were incubated in a humidified atmosphere of 5% CO₂at 37° C. Prior to use in the assay, A549 cells were washed with PBS andtrypsinized (Mediatech Inc., Cat. No. 25-052-CI) to lift the cells. Thetrypsin cell suspension was neutralized with complete F12K media andcentrifuged to pellet the cells. The cell pellet was resuspended incomplete F12K media at a concentration of 2.0×10⁵/mL. Cells were seededat 20,000 per well, 100 μL total volume, in a flat bottom tissue cultureplate and allowed to adhere overnight.

On day two, A549 cells were pre-incubated with test compound or DMSO(control) (Sigma-Aldrich, St. Louis, Mo., Catalog No. D2650) for 1 hour.The cells were then stimulated with IFNγ (75 ng/mL) (Peprotech Inc.,Rocky Hill, N.J., Cat. No. 300-02) and allowed to incubate for 24 hours.The final test compound dose range was 30 μM to 14 nM in 200 μL F12Kmedia containing 5% FBS, 0.3% DMSO.

On day three, the cell media was removed and the cells were washed with200 μL PBS (phosphate buffered saline). Each well was trypsinized todissociate the cells, then neutralized by addition of 200 μL completeF12K media. Cells were pelleted and stained with an APC conjugated mouseanti-human ICAM-1 (CD54) (BD Pharmingen, San Diego, Calif., Catalog#559771) antibody for 20 minutes at 4° C. Cells were washed with icecold FACS buffer (PBS+2% FBS) and surface ICAM-1 expression was analyzedby flow cytometry. Detection was performed using a BD LSR I System FlowCytometer, purchased from BD Biosciences of San Jose, Calif. Events weregated for live scatter and the geometric mean was calculated(Becton-Dickinson CellQuest software version 3.3, Franklin Lakes, N.J.).Geometric means were plotted against the compound concentration togenerate a dose response curve.

E. Example 5 U937 IFNγ ICAM1 FACS Assay

Human U937 monocytic cells up-regulate ICAM-1 (CD54) surface expressionin response to a variety of different stimuli. Therefore, using ICAM-1expression as readout, compound effects on different signaling pathwayscan be assessed in the same cell type. IFNγ up-regulates ICAM-1 throughactivation of the JAK/Stat pathway. In this example, the up-regulationof ICAM-1 by IFNγ was assessed.

The U937 human monocytic cell line was obtained from ATCC of RockvilleMd., catalog number CRL-1593.2, and cultured in RPM1-1640 mediumcontaining 10% (v/v) FCS. U937 cells were grown in 10% RPMI. The cellswere then plated at a concentration of 100,000 cells per 160 μL in 96well flat bottom plates. The test compounds were then diluted asfollows: 10 mM test compound was diluted 1:5 in DMSO (3 μL 10 mM testcompound in 12 μL DMSO), followed by a 1:3 serial dilution of testcompound in DMSO (6 μL test compound serially diluted into 12 μL DMSO togive 3-fold dilutions). Then 4 μL of test compound was transferred to 76μL of 10% RPMI resulting in a 10× solution (100 μM test compound, 5%DMSO). For control wells, 4 μL of DMSO was diluted into 76 μL 10% RPMI.

The assay was performed in duplicate with 8 points (8 3-fold dilutionconcentrations from 10 μL) and with 4 wells of DMSO only (control wells)under stimulated conditions and 4 wells of DMSO only under unstimulatedconditions.

The diluted compound plate was mixed 2× using a multimek (BeckmanCoulter of Brea, Calif.) and then 20 μL of the diluted compounds wastransferred to the 96 well plate containing 160 μL of cells, which werethen mixed again twice at low speeds. The cells and compounds were thenpre-incubated for 30 minutes at 37° C. with 5% CO₂.

The 10× stimulation mix was made by preparing a 100 ng/mL solution ofhuman IFNγ in 10% RPMI. The cells and compound were then stimulated with20 μL of IFNγ stimulation mix to give a final concentration of 10 ng/mLIFNγ, 10 μM test compound, and 0.5% DMSO. The cells were kept underconditions for stimulation for 18-24 hours at 37° C. with 5% CO₂.

The cells were transferred to a 96 well round bottom plate for stainingand then kept on ice for the duration of the staining procedure. Cellswere spun down at 1000 rpm for 5 minutes at 4° C., following which thesupernatant was removed. Following removal of the supernatant, 1 μL APCconjugated mouse anti-human ICAM-1 antibody was added per 100 μL FACSbuffer. The cells were then incubated on ice in the dark for 30 minutes.Following incubation, 150 μL of FACS buffer was added and the cells werecentrifuged at 1000 rpm for 5 minutes at 4° C., following which thesupernatant was removed. After removal of the supernatant, 200 μL ofFACS buffer was added and the cells were resuspended. After suspension,the cells were centrifuged at 1000 rpm for 5 min at 4° C. Supernatantwas then removed prior to resuspension of the cells in 150 μL FACSbuffer.

Detection was performed using a BD LSR I System Flow Cytometer,purchased from BD Biosciences of San Jose, Calif. The live cells weregated for live scatter and the geometric mean of ICAM-APC was measured(Becton-Dickinson CellQuest software version 3.3, Franklin Lakes, N.J.).Both % live cells and ICAM-1 expression was analyzed. The assays for thetest compounds were carried out in parallel with a control compound ofknown activity. The EC₅₀ for the control compound is typically 40-100nM.

F. Example 6 Fluorescence Polarization Kinase Assay

This assay may be utilized to determine the potency of a compound of theinvention against certain JAK kinases and the selectivity of a compoundof the invention in inhibiting certain JAK kinase activity in vitro.

Reagents and Buffers

Tyrosine Kinase Kit Green (Invitrogen, Cat# P2837)

Acetylated Bovine Gamma Globulin (BGG) (Invitrogen, Cat# P2255)

Active JAK1 (Carna Biosciences)

Active JAK2 (Carna Biosciences)

Active JAK3 (Carna Biosciences)

TK2 Peptide (Biotin-EGPWLEEEEEAYGWMDF-CONH₂) (SynPep Custom Synthesis)

Methods

Test compounds were serially diluted in DMSO starting from 500× thedesired final concentration and then diluted to 1% DMSO in kinase buffer(20 mM HEPES, pH 7.4, 5 mM MgCl₂, 2 mM MnCl₂, 1 mM DTT, 0.1 mg/mLacetylated BGG). Test compound in 1% DMSO (0.2% DMSO final) was mixedwith ATP and substrate in kinase buffer at ambient temperature.

The kinase reactions were performed in a final volume of 20 μLcontaining peptide substrate and ATP and started by addition of kinasein kinase buffer. The reactions were allowed to proceed at ambienttemperature. Final substrate, ATP and enzyme concentrations and reactiontimes for the different kinase assays are listed in Table X.

TABLE X FINAL SUBSTRATE, ATP, ENZYME CONCENTRATIONS AND REACTION TIMESEnzyme Amount per Sub- Substrate ATP Assay Enzyme Reaction strateConcentration Concentration Time JAK1 20 ng TK2 10 μM 5 μM 20 min JAK20.3 ng  TK2 10 μM 5 μM 20 min JAK3  2 ng TK2 10 μM 5 μM 20 min

The reactions were stopped by adding 20 μL of PTK quench mix containingEDTA/anti-phosphotyrosine antibody (1× final)/fluorescent phosphopeptidetracer (0.5× final) diluted in FP Dilution Buffer according tomanufacturer's instructions (Invitrogen). The plates were incubated for30 minutes in the dark at ambient temperature and then read on aPolarion fluorescence polarization plate reader (Tecan).

Data were converted to amount of phosphopeptide present using acalibration curve generated by competition with the phosphopeptidecompetitor provided in the Tyrosine Kinase Assay Kit, Green(Invitrogen). For IC₅₀ determination, the compounds were tested ateleven concentrations in duplicate and curve-fitting was performed bynon-linear regression analysis using Matlab version 6.5 (MathWorks,Inc., Natick, Mass., USA).

G. Example 7 Proliferation Assay

Reagents and Buffers

Dimethyl Sulfoxide (DMSO) (Sigma-Aldrich, Cat No. D2650) (Control)

Iscove's DMEM, ATCC Catalog #30-2005

1 M HEPES, Cellgro Catalog #25-060-CI (100 mL)

100 mM Sodium Pyruvate, Cellgro Catalog #25-000-CI (100 mL)

Penicillin/Streptomycin, 10000 U/mL each, Cellgro Catalog #30-002-CI(100 mL)

RPMI 1640 (Cellgro, Cat No. 10-040-CM)

Fetal Bovine Serum (JRH, Cat No. 12106-500M)

Donor Equine Serum, Hyclone Catalog #SH30074.02 (100 mL)

50 μM hydrocortisone solution, Sigma Catalog #H6909-10 ml (10 mL)

Culture Conditions

BaF3 V617F cells are maintained and plated in RPMI with 10% FBS. Platingdensity for these cells is 1×10⁵ cells/mL.

UKE-1 are maintained and plated in Iscove's DMEM containing 10% FBS, 10%equine serum, 1% penicillin/streptomycin and 1 uM hydrocortisone.Plating density for these cells is 0.4×10⁶ cells/mL

Methods

The cells were resuspended in a corresponding medium at a required celldensity (see above). 100μ of cell suspension was added to each well of aflat bottom 96 well white plate. The compound was serially diluted inDMSO from 5 mM in 3-fold dilutions, and then diluted 1:250 in the RPMI1640 medium containing 5% FBS and pen/strep. 100 μL of resulting 2×compound solution was added per well in duplicate and the cells wereallowed to proliferate for 72 hours at 37° C.

Proliferation was measured using Cell Titer-Glo. The substrate wasthawed and allowed to come to room temperature. After removal of top 100μL of medium from each well, 100 μL of the premixed Cell Titer-Gloreagent was added to each well. The plates were mixed on an orbitalshaker for three minutes to induce lysis and incubated at ambienttemperature for an additional five minutes to allow the signal toequilibrate. The Luminescence was read on the Wallac Plate Reader.

The results of the ability of the compounds of the invention to inhibitJAK2 activity, when tested in the above assay, are shown in thefollowing Table XI wherein the level of activity (i.e., the IC₅₀) foreach compound is indicated in Table XI. The compound numbers in Table XIrefers to the compounds disclosed herein as being prepared by themethods disclosed herein:

TABLE XI ID Example 2 Example 7 II-45 8888 II-46 0.59226 II-47 0.48681II-48 0.69758 II-49 0.33885 II-50 0.47181 II-51 1.07395 II-52 6.12462II-53 1.98186 II-54 1.97378 II-55 8.8755 II-56 0.63895 II-57 1.70402II-58 16.1682 II-59 3.13733 II-60 0.39121 II-61 5.96921 II-62 0.43797II-63 0.53012 II-64 0.54774 II-65 0.32656 II-66 0.46729 II-67 0.71682II-68 4.13609 II-69 1.80964 II-70 1.38532 II-71 1.39745 II-72 18.3231II-73 0.59514 II-74 1.49124 II-75 10.382 II-76 1.31395 II-77 1.31728II-78 0.37115 II-79 3.16136 I-1 0.13987 I-2 0.18084 III-1 0.2901 2.97058III-2 0.91052 6.17772 I-3 0.15302 I-4 0.09552 I-5 0.0316 I-6 8.79923 I-75.82401 VIII-8 5.11353 I-8 8888 I-9 99.5913 I-10 64.1862 I-11 15.947VIII-1 V-1 0.40087 VIII-3 0.71702 V-2 1.22476 0.80698 V-3 1.63748 V-40.68606 V-5 0.99929 V-6 1.11582 V-7 1.60377 V-8 3.03243 V-9 2.20378 V-100.67265 V-11 2.16054 V-12 0.66839 V-13 19.2616 V-14 2.68653 II-800.18796 II-81 1.09596 II-82 0.79697 II-83 1.39034 II-84 38.2625 II-852.68705 II-86 0.72402 II-87 5.2717 II-88 0.83327 II-89 0.6737 II-900.08362 II-91 0.14161 II-92 0.558 II-93 0.35039 II-94 13.5176 II-950.2504 II-96 0.09101 II-97 3059.28 II-98 0.26367 II-99 0.10251 II-1000.17852 II-101 0.19391 II-102 1.17434 II-103 0.50859 II-104 0.34863II-105 20.2749 II-106 0.38342 II-107 0.31623 II-108 0.085 II-109 0.1508II-110 0.60132 II-111 8888 II-112 0.43122 II-113 0.28597 II-114 0.1797II-115 0.40872 II-116 0.07366 II-117 0.20759 II-118 0.22882 II-1191.36223 II-120 0.87108 II-121 0.36349 II-122 0.27611 II-123 0.37299II-124 1.15538 II-125 0.51189 I-14 0.22457 II-126 1.51493 II-127 0.33785II-128 0.75511 II-129 0.1269 II-130 0.14003 II-131 0.15147 II-1321.62949 II-133 0.20887 II-134 0.23106 II-135 0.26704 II-136 2.14234II-137 0.54131 II-138 0.72629 II-139 4.32931 II-140 0.25062 II-1410.07391 II-142 0.48514 II-143 0.25197 II-144 0.54869 II-145 3.97911II-146 0.22513 II-147 0.14182 II-148 1.32484 II-149 1.03999 II-1500.30728 II-151 0.39758 II-152 0.35686 II-153 3.33027 II-154 0.04288II-155 0.0831 II-156 0.05807 II-157 0.13778 II-158 0.15817 II-1590.04761 II-160 0.02994 II-161 0.14917 II-162 0.1344 II-163 0.06363II-164 0.09476 II-165 0.32338 II-166 0.24662 II-167 0.20485 II-1682.04671 II-169 0.34795 II-170 0.0402 II-171 0.73456 II-172 2.2587 II-1732.33729 II-174 0.12656 II-175 0.35381 II-176 0.19033 II-177 0.64292II-178 0.42799 II-179 0.2146 II-180 0.63317 II-181 4.33459 II-1820.71092 II-183 0.14242 VI-1 0.4734 VI-2 2.7976 VI-3 1.27378 VI-4 1.20539VI-5 0.79782 I-22 0.54903 II-184 0.89208 II-185 0.11003 I-12 1.11271I-13 0.54887 VIII-4 0.24159 VIII-5 0.0709 VIII-6 0.34932 II-1 0.122970.40517 II-2 0.61438 9999 II-3 0.11643 5782.26 II-4 0.08797 3.40074 II-50.36363 6.06224 VIII-2 1.92022 56.1226 II-6 0.03637 0.1375 II-7 0.044870.68801 II-8 0.03616 0.19973 II-9 0.08262 0.40818 II-10 0.05775 0.7077II-11 0.25364 2.79756 II-12 0.10133 0.12967 II-13 0.12635 0.35854 II-140.15235 2.18582 II-15 0.07815 8.06379 II-16 0.26526 3.29388 II-170.08708 2.94713 II-18 0.27863 9999 II-19 0.10605 2.20657 II-20 0.505019999 II-21 0.10995 0.47902 II-22 0.30229 2.69379 II-23 0.10666 6.13742II-24 0.27974 9999 II-25 0.14207 2.30014 II-26 0.1465 2.23914 II-2789.2129 9999 II-28 0.2333 10.866 II-29 0.07864 12.4862 II-30 0.09461.12815 II-31 0.03571 2.12674 II-32 0.05228 1.52899 II-33 0.020340.69812 II-34 0.04555 0.46042 II-35 0.04886 0.91192 II-36 0.0381 0.59925II-37 0.01833 0.87486 II-38 0.33079 1.5392 II-39 0.32663 2.03907 II-400.70394 2.20234 VIII-7 0.1101 0.4783 II-41 0.0378 0.1232 II-42 0.024710.06369 II-43 0.03865 0.02388 II-44 0.07828 0.4883 III-3 0.04939 5.79824III-4 0.15116 3.43522 III-5 0.17777 6.31159 III-6 0.02655 1.44918 IV-10.0747 IV-2 0.04398 IV-3 0.17765 IV-4 0.12681 IV-5 0.08727 IV-6 0.20711IV-7 0.11581 0.79563 IV-8 0.25696 IV-9 0.73117 IV-10 0.73569 IV-110.30212 IV-12 1.67742 IV-13 0.27737 IV-14 0.26249 IV-15 0.49306 IV-160.84537 VIII-9 0.17892 VIII-10 0.71637 I-18 0.83165 I-19 0.60281 III-70.64438 II-186 0.1281 II-187 0.2929 II-188 0.22357 II-189 0.54572 II-1900.70141 II-191 0.46649 II-192 0.37817 II-193 1.29879 II-194 1.34459II-195 0.18037 II-196 0.59689 II-197 0.09196 II-198 0.11613 II-1990.05725 II-200 0.27607 II-201 0.17362 II-202 1.44167 II-203 1.5024II-204 0.17527 II-205 0.13487 II-206 1.56005 II-207 0.38359 II-208II-209 0.31677 II-210 0.16717 II-211 0.03939 II-212 2.20194 II-2132.49021 II-214 0.05555 I-15 0.22529 I-16 17.694 I-17 0.99016 VIII-110.38765 VIII-12 0.87885 II-215 1.52288 II-216 0.24621 II-217 0.23279II-218 0.24752 II-219 0.11357 II-220 0.12088 II-221 0.23832 II-2220.9458 II-223 0.73342 II-224 0.84791 II-225 0.1198 VII-1 0.2289 VII-20.37076 VII-3 1.16636 VII-4 0.55779 VII-5 13.2023 VII-6 1.89916 VII-75.39145 VII-8 1.60674 VII-9 1.33727 VII-10 0.14377 I-20 0.18854 I-210.24327

1. A method of inhibiting an activity of a JAK kinase, comprisingcontacting a cell comprising the JAK kinase with an amount of a compoundeffective to inhibit an activity of the JAK kinase wherein the compoundis according to formula I:

or pharmaceutically acceptable salt thereof, wherein: ring A is aryl orheteroaryl; ring B is aryl, heteroaryl, cycloalkyl, or heterocyclic; pis 0, 1, 2 or 3 when ring A is monocyclic or p is 0, 1, 2, 3, 4, or 5when ring A contains multiple rings; q is 0, 1, 2 or 3 when ring B ismonocyclic or q is 0, 1, 2, 3, 4, or 5 when ring B contains multiplerings; X is selected from the group consisting of alkyl, substitutedalkyl, hydroxy, alkoxy, substituted alkoxy, amino, substituted amino,carboxyl, carboxyl ester, cyano, halo, nitro, alkenyl, substitutedalkenyl, alkynyl, and substituted alkynyl; W is —SO₂N(R⁴)R⁵,-alk-SO₂N(R⁴)R⁵, —N(R⁴)SO₂R⁵, or -alk-N(R⁴)SO₂R⁵; -alk- is selected fromthe group consisting of straight or branched chain C₁₋₆ alkylene group,and straight or branched chain substituted C₁₋₆ alkylene group; R¹ ishydrogen or C₁₋₃ alkyl; each R² independently is selected from the groupconsisting of alkyl, substituted alkyl, alkoxy, substituted alkoxy,alkenyl, substituted alkenyl, alkynyl, substituted alkynyl,cycloalkenyl, substituted cycloalkenyl, alkynyloxy, amino, substitutedamino, aryl, substituted aryl, aryloxy, substituted aryloxy, cyano,cycloalkyl, substituted cycloalkyl, cycloalkoxy, substitutedcycloalkoxy, heteroaryl, substituted heteroaryl, heteroaryloxy,substituted heteroaryloxy, heterocyclic, substituted heterocyclic,heterocyclyloxy, substituted heterocyclyloxy, aminocarbonyl,aminocarbonyloxy, carboxyl, carboxyl ester, (carboxyl ester)oxy, nitro,halo, and oxo, wherein if R² is oxo, then the oxo substituent isattached to a nonaromatic portion of ring A; or R⁴ and one of R²together with the intervening atoms bound thereto form a heterocyclic ora substituted heterocyclic fused to ring A; or R⁵ and one of R² togetherwith the intervening atoms bound thereto form a heterocyclic or asubstituted heterocyclic fused to ring A; each R³ independently isselected from the group consisting of alkyl, substituted alkyl, alkoxy,substituted alkoxy, alkenyl, substituted alkenyl, alkynyl, substitutedalkynyl, alkynyloxy, amino, substituted amino, aryl, substituted aryl,aryloxy, substituted aryloxy, cyano, cycloalkyl, substituted cycloalkyl,cycloalkoxy, substituted cycloalkoxy, heteroaryl, substitutedheteroaryl, heteroaryloxy, substituted heteroaryloxy, heterocyclic,substituted heterocyclic, heterocyclyloxy, substituted heterocyclyloxy,aminocarbonyl, aminocarbonyloxy, carboxyl, carboxyl ester, (carboxylester)oxy, nitro, and halo; R⁴ is selected from the group consisting ofhydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl,heterocyclic, substituted heterocyclic, aryl, substituted aryl,heteroaryl, substituted heteroaryl, acyl and M⁺, wherein M⁺is acounterion selected from the group consisting of K⁺, Na⁺, Li⁺ and⁺N(R⁸)₄, wherein R⁸ is hydrogen or alkyl, and the nitrogen of—SO₂N(R⁴)R⁵ or —N(R⁴)SO₂R⁵ is N⁻; R⁵ is selected from the groupconsisting of hydrogen, alkyl, substituted alkyl, amino, alkylamino,dialkylamino, cycloalkylamino, cycloalkyl, substituted cycloalkyl,heterocyclic, substituted heterocyclic, aryl, substituted aryl,heteroaryl, substituted heteroaryl, and acyl; or R⁴ and R⁵ together withthe intervening atom or atoms bound thereto form a heterocyclic or asubstituted heterocyclic group; provided: a) when W is —SO₂N(R⁴)R⁵, thenW is not bound to an atom adjacent to the atom of ring A that is boundto N4 of the pyrimidine; b) when W is —N(R⁴)SO₂R⁵, then A is notchromanyl; c) when W is —SO₂N(R⁴)R⁵ and X is halo or alkyl, then R³ isnot methoxy; and d) when W is —SO₂N(R⁴)R⁵ and X is bromo, then R³ is notalkoxy, substituted alkoxy or halo.
 2. The method of claim 1, wherein Ais phenyl.
 3. The method of claim 1, wherein A-W is:

wherein p is zero.
 4. The method of claim 1, wherein B is aryl orheteroaryl.
 5. The method of claim 4, wherein B—(R³)_(q) is selectedfrom the group consisting of:

wherein Q is carbon or nitrogen.
 6. The method of claim 1, wherein thecompound is represented by formula II:

wherein: R¹ is selected from the group consisting of hydrogen and C₁₋₃alkyl; R² is selected from the group consisting of alkyl, substitutedalkyl, alkoxy, substituted alkoxy, and halo; R³ is selected from thegroup consisting of alkyl, substituted alkyl, alkoxy, substitutedalkoxy, halo, cyano, cycloalkyl, substituted cycloalkyl, heterocyclic,substituted heterocyclic, aminocarbonyl, heteroaryl, substitutedheteroaryl, aryl, and substituted aryl; X is alkyl, substituted alkyl,fluoro, chloro, bromo, amino, or substituted amino; -alk- is methyleneor ethylene; R⁴ is hydrogen, alkyl, substituted alkyl, cycloalkyl, orsubstituted cycloalkyl; and R⁵ is hydrogen, alkyl, substituted alkyl,cycloalkyl, or substituted cycloalkyl.
 7. The method of claim 6, whereinR¹ is hydrogen; R³ is methyl, methoxy, or substituted methoxy; R⁴ and R⁵independently are selected from the group consisting of hydrogen, alkyl,substituted alkyl substituted with alkynyl, and cyclopropyl; p is 0; andq is 1, 2 or
 3. 8. The method of claim 1, wherein the compound isrepresented by formula IIa:

wherein: R¹ is hydrogen or C₁₋₂ alkyl; R² is alkyl; R³ is selected fromthe group consisting of alkyl, substituted alkyl, alkoxy, andsubstituted alkoxy; X is alkyl, substituted alkyl, fluoro, chloro,bromo, amino, or substituted amino; R⁴ is hydrogen, alkyl, substitutedalkyl, cyclopropyl, or substituted cyclopropyl; and R⁵ is hydrogen,alkyl, substituted alkyl, cyclopropyl, or substituted cyclopropyl. 9.The method of claim 8, wherein R¹ is hydrogen or methyl; R² is methyl;R³ is methyl, methoxy, or substituted methoxy substituted with alkynyl,aminocarbonyl, or heteroaryl; X is methyl, fluoro, trifluoromethyl, oramino; -alk- is methylene; R⁴ and R⁵ independently are selected from thegroup consisting of hydrogen, alkyl, substituted alkyl substituted withalkynyl, and cyclopropyl; p is 0 or 1; and q is 1, 2 or
 3. 10. Themethod of claim 1, wherein the compound is represented by formula III:

wherein: W is —N(R⁴)SO₂R⁵, or -alk-N(R⁴)SO₂R⁵; p is 0 or 1; q is 1, 2,or 3; R³ is selected from the group consisting of alkyl, substitutedalkyl, alkoxy, substituted alkoxy, halo, cyano, cycloalkyl, substitutedcycloalkyl, heterocyclic, substituted heterocyclic, aminocarbonyl,heteroaryl, substituted heteroaryl, aryl, and substituted aryl; X isalkyl, substituted alkyl, fluoro, chloro, or bromo; -alk- is methyleneor ethylene; and R⁴ and R⁵ independently are selected from the groupconsisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, andsubstituted cycloalkyl.
 11. The method of claim 10, wherein R³ isselected from the group consisting of alkyl, substituted alkyl, alkoxy,substituted alkoxy, halo, cyano, heterocyclic, substituted heterocyclic,aminocarbonyl, heteroaryl, and substituted heteroaryl; X is methyl,fluoro, or chloro; -alk- is methylene; R⁴ and R⁵ independently areselected from the group consisting of hydrogen, alkyl, and cyclopropyl.12. The method of claim 11, wherein —N(R⁴)SO₂R⁵ is —N(H)SO₂-cyclopropyl.13. The method of claim 1, wherein the compound is represented byformula IV:

wherein: Q is carbon or nitrogen; X is alkyl, substituted alkyl, fluoro,chloro, or bromo; -alk- is methylene; R³ is selected from the groupconsisting of alkyl, substituted alkyl, heterocyclic, substitutedheterocyclic, and aminocarbonyl; and R⁴ and R⁵ independently areselected from the group consisting of hydrogen, alkyl, substitutedalkyl, cycloalkyl, and substituted cycloalkyl.
 14. The method of claim1, wherein the compound is represented by formula V:

wherein Q is carbon or nitrogen; X is alkyl, substituted alkyl, or halo;-alk- is methylene; R³ is selected from the group consisting of alkyl,substituted alkyl, alkoxy, substituted alkoxy, halo, cycloalkyl,substituted cycloalkyl, heterocyclic, substituted heterocyclic,aminocarbonyl, heteroaryl, substituted heteroaryl, aryl, and substitutedaryl; and R⁴ and R⁵ independently are selected from the group consistingof hydrogen, alkyl, substituted alkyl, cycloalkyl, and substitutedcycloalkyl.
 15. The method of claim 1, wherein the compound isrepresented by formula VI:

wherein X is alkyl or halo; and R³ is selected form the group consistingof alkyl, alkoxy, halo, heterocyclic and heteroaryl and R⁵ is alkyl orcycloalkyl.
 16. The method of claim 1, wherein the compound isrepresented by formula VII:

wherein: X is halo, Z is CH; R³ is selected form the group consisting ofalkyl, alkoxy, halo, heterocyclic and heteroaryl; and R⁵ is alkyl orcycloalkyl.
 17. The method of claim 1, wherein the compound isrepresented by formula VIII:

wherein Z is CH; X is alkyl or halo; and R³ is alkyl, alkoxy orheterocyclic.
 18. The method of claim 1, wherein the compound isselected from the group consisting of:

or pharmaceutically acceptable salt thereof.
 19. The method of claim 1,wherein the compound is selected from the group consisting of: I-1:5-Fluoro-N4-[3-(prop-2-ynylaminosulfonyl)phenyl]-N2-(3,4,5-trimethoxyphenyl)-2,4-pyrimidinediamine;I-2:N4-(3-Aminosulfonyl-4-methylphenyl)-5-methyl-N2-[4-(prop-2-ynyloxy)phenyl]-2,4-pyrimidinediamine;I-3:N4-(3-Aminosulfonyl-4-methylphenyl)-N2-[4-(prop-2-ynyloxy)phenyl]-5-trifluoromethyl-2,4-pyrimidinediamine;I-4:N2-(3,5-Dimethyl-4-methoxyphenyl)-5-fluoro-N4-[3-(prop-2-ynylaminosulfonyl)phenyl]-2,4-pyrimidinediamine;I-5:N2-(3,5-Dimethyl-4-methoxyphenyl)-5-fluoro-N4-[4-(prop-2-ynylaminosulfonyl)phenyl]-2,4-pyrimidinediamine;I-6:5-Amino-N4-(4-aminosulfonylphenyl)-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine;I-7:5-Amino-N4-(3-aminosulfonylphenyl)-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine;I-8:5-Amino-N4-(3-aminosulfonylphenyl)-N2-(4-methoxyphenyl)-N2-methyl-2,4-pyrimidinediamine;I-9:5-Amino-N4-(4-aminosulfonylphenyl)-N2-(4-methoxyphenyl)-N2-methyl-2,4-pyrimidinediamine;II-1:N4-(4-cyclopropylsulfonylaminomethyl)phenyl-5-fluoro-N2-(3,4,5-trimethoxy)phenyl-2,4-pyrimidinediamine;I-10:5-Amino-N4-(3-aminosulfonylphenyl)-N2-(3-methoxyphenyl)-N2-methyl-2,4-pyrimidinediamine;I-11:5-Amino-N4-(4-aminosulfonylphenyl)-N2-(3-methoxyphenyl)-N2-methyl-2,4-pyrimidinediamine;I-12:N4-(3-Aminosulfonylphenyl)-N2-[4-(2-pyridinyl)methyleneoxyphenyl]-5-trifluoromethyl-2,4-pyrimidinediamine;I-13:N4-[4-N-(Cyclopropyl)aminosulfonylphenyl]-N2-[4-(3-pyridinyl)methyleneoxyphenyl]-5-trifluoromethyl-2,4-pyrimidinediamine;I-14:N4-[(3-(1,1-Dimethylamino)sulfonyl)phenyl]-5-methyl-N2-[4-(4-methyl-1-piperazinyl)phenyl]-2,4-pyrimidinediamine;I-15:5-Chloro-N4-[3-(N-tert-butylsulfonyl)phenyl]-N2-[3,4,5-trimethoxyphenyl]-2,4-pyrimidinediamine;I-16:5-Chloro-N4-[3-(N-tert-butylsulfonyl)phenyl]-N2-[3,4-trimethyl-4-methoxyphenyl]-2,4-pyrimidinediamine;I-17:5-Chloro-N4-[3-(N-tert-butylsulfonyl)phenyl]-N2-[4-(N-methylpiperidin-4-yl)phenyl]-2,4-pyrimidinediamine;I-18:5-Bromo-N4-[3-(N-tert-butylsulfonyl)phenyl]-N2-[4-(4-methylpiperazine)-phenyl]-2,4-pyrimidinediamine;I-19:N4-[3-(N-tert-butylsulfonyl)phenyl]-N2-[4-(4-methylpiperazine)-phenyl]-2,4-pyrimidinediamine;I-20:5-Methyl-N4-[3-(N-tert-butylsulfonyl)phenyl]-N2-[3,5-dimethyl-4-(2-(1-morpholino)ethoxyphenyl]-2,4-pyrimidinediamine;I-21:5-Chloro-N4-[3-(N-tert-butylsulfonyl)phenyl]-N2-[3,5-dimethyl-4-(2-(1-morpholino)ethoxyphenyl]-2,4-pyrimidinediamine;I-22:5-Chloro-N4-[(3-(1,1-dimethylethylamino)sulfonyl)phenyl]-N2-[3-methyl-4-[(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]phenyl]-2,4-pyrimidinediamine;II-2:N4-(4-cyclopropylsulfonylaminomethyl)phenyl-N2-(3,4-difluoro)phenyl-5-fluoro-2,4-pyrimidinediamine;II-3:N2-(3-chloro-4-methoxy)phenyl-N4-(4-cyclopropylsulfonylaminomethyl)phenyl-5-fluoro-2,4-pyrimidinediamine;II-4:N4-(4-cyclopropylsulfonylaminomethyl)phenyl-N2-(3,5-dimethyl)phenyl-5-fluoro-2,4-pyrimidinediamine;II-5:N2-(3-chloro-4-cyano)phenyl-N4-(4-cyclopropylsulfonylaminomethyl)phenyl-5-fluoro-2,4-pyrimidinediamine;II-6:N4-(4-cyclopropylsulfonylaminomethyl)phenyl-N2-[4-(4-ethylpiperazino)-3-methyl]phenyl-5-fluoro-2,4-pyrimidinediamine;II-7:N4-(4-cyclopropylsulfonylaminomethyl)phenyl-N2-(3,5-dimethyl)phenyl-5-methyl-2,4-pyrimidinediamine;II-8:N4-(4-cyclopropylsulfonylaminomethyl)phenyl-N2-[4-(4-ethylpiperazino)-3-methyl]phenyl-5-methyl-2,4-pyrimidinediamine;II-9:N4-(4-cyclopropylsulfonylaminomethyl)phenyl-5-methyl-N2-(3,4,5-trimethoxy)phenyl-2,4-pyrimidinediamine;II-10:N2-(3-chloro-4-methoxy)phenyl-N4-(4-cyclopropylsulfonylaminomethyl)phenyl-5-methyl-2,4-pyrimidinediamine;II-11:N4-(3-cyclopropylsulfonylaminomethyl)phenyl-N2-(3,5-dimethyl)phenyl-5-methyl-2,4-pyrimidinediamine;II-12:N4-(3-cyclopropylsulfonylaminomethyl)phenyl-N2-[4-(4-ethylpiperazino)-3-methyl]phenyl-5-methyl-2,4-pyrimidinediamine;II-13:N4-(3-cyclopropylsulfonylaminomethyl)phenyl-5-methyl-N2-(3,4,5-trimethoxy)phenyl-2,4-pyrimidinediamine;II-14:N2-(3-chloro-4-methoxy)phenyl-N4-(3-cyclopropylsulfonylaminomethyl)phenyl-5-methyl-2,4-pyrimidinediamine;II-15:N2-(4-aminocarbonyl)phenyl-N4-(4-cyclopropylsulfonylaminomethyl)phenyl-5-fluoro-2,4-pyrimidinediamine;II-16:N2-(3-aminocarbonyl)phenyl-N4-(4-cyclopropylsulfonylaminomethyl)phenyl-5-fluoro-2,4-pyrimidinediamine;II-17:N2-(4-aminocarbonyl)phenyl-N4-(3-chloro-4-cyclopropylsulfonylaminomethyl)phenyl-5-methyl-2,4-pyrimidinediamine;II-18:N2-(3-aminocarbonyl)phenyl-N4-(3-chloro-4-cyclopropylsulfonylaminomethyl)phenyl-5-methyl-2,4-pyrimidinediamine;II-19:N2-(4-aminocarbonyl)phenyl-N4-[4-(N-cyclopropylsulfonyl-N-methyl)aminomethyl]phenyl-5-methyl-2,4-pyrimidinediamine;II-20:N2-(3-aminocarbonyl)phenyl-N4-[4-(N-cyclopropylsulfonyl-N-methyl)aminomethyl]phenyl-5-methyl-2,4-pyrimidinediamine;II-21:N2-(4-aminocarbonyl)phenyl-N4-[3-(N-cyclopropylsulfonyl-N-methyl)aminomethyl]phenyl-5-methyl-2,4-pyrimidinediamine;II-22:N2-(3-aminocarbonyl)phenyl-N4-[3-(N-cyclopropylsulfonyl-N-methyl)aminomethyl]phenyl-5-methyl-2,4-pyrimidinediamine;II-23:N2-(4-aminocarbonyl)phenyl-N4-(3-cyclopropylsulfonylaminomethyl)phenyl-5-methyl-2,4-pyrimidinediamine;II-24:N2-(3-aminocarbonyl)phenyl-N4-(3-cyclopropylsulfonylaminomethyl)phenyl-5-methyl-2,4-pyrimidinediamine;II-25:N2-(4-cyano)phenyl-N4-(3-cyclopropylsulfonylaminomethyl)phenyl-5-methyl-2,4-pyrimidinediamine;II-26:N2-(3-cyano)phenyl-N4-(3-cyclopropylsulfonylaminomethyl)phenyl-5-methyl-2,4-pyrimidinediamine;II-27:N2-(4-cyano)phenyl-N4-[4-(N-cyclopropylsulfonyl-N-methyl)aminomethyl]phenyl-5-methyl-2,4-pyrimidinediamine;II-28:N2-(3-cyano)phenyl-N4-[4-(N-cyclopropylsulfonyl-N-methyl)aminomethyl]phenyl-5-methyl-2,4-pyrimidinediamine;II-29:N2-(4-cyano)phenyl-N4-(4-cyclopropylsulfonylaminomethyl)phenyl-5-fluoro-2,4-pyrimidinediamine;II-30:N2-(3-cyano)phenyl-N4-(4-cyclopropylsulfonylaminomethyl)phenyl-5-fluoro-2,4-pyrimidinediamine;II-31:N2-(4-aminocarbonyl)phenyl-N4-(4-cyclopropylsulfonylaminomethyl)phenyl-5-methyl-2,4-pyrimidinediamine;II-32:N2-(3-aminocarbonyl)phenyl-N4-(4-cyclopropylsulfonylaminomethyl)phenyl-5-methyl-2,4-pyrimidinediamine;II-33:N2-(4-cyano)phenyl-N4-(4-cyclopropylsulfonylaminomethyl)phenyl-5-methyl-2,4-pyrimidinediamine;II-34:N2-(3-cyano)phenyl-N4-(4-cyclopropylsulfonylaminomethyl)phenyl-5-methyl-2,4-pyrimidinediamine;II-35:5-chloro-N2-(3-chloro-4-methoxy)phenyl-N4-(4-cyclopropylsulfonylaminomethyl)phenyl-2,4-pyrimidinediamine;II-36:5-chloro-N4-(4-cyclopropylsulfonylaminomethyl)phenyl-N2-(3,5-dimethyl)phenyl-2,4-pyrimidinediamine;II-37:N2-(4-aminocarbonyl)phenyl-5-chloro-N4-(4-cyclopropylsulfonylaminomethyl)phenyl-2,4-pyrimidinediamine;II-38:N4-(3-chloro-4-cyclopropylsulfonylaminomethyl)phenyl-N2-(3,5-dimethyl)phenyl-5-methyl-2,4-pyrimidinediamine;II-39:N4-[4-(N-cyclopropylsulfonyl-N-methyl)aminomethyl]phenyl-N2-(3,5-dimethyl)phenyl-5-methyl-2,4-pyrimidinediamine;II-40:N4-[3-(N-cyclopropylsulfonyl-N-methyl)aminomethyl]phenyl-N2-(3,5-dimethyl)phenyl-5-methyl-2,4-pyrimidinediamine;II-41:N4-(4-cyclopropylsulfonylaminomethyl)phenyl-N2-(3,5-dimethyl-4-methoxy)phenyl-5-fluoro-2,4-pyrimidinediamine;II-42:N4-(4-cyclopropylsulfonylaminomethyl)phenyl-N2-(3,5-dimethyl-4-methoxy)phenyl-5-methyl-2,4-pyrimidinediamine;II-43:5-chloro-N4-(4-cyclopropylsulfonylaminomethyl)phenyl-N2-(3,5-dimethyl-4-methoxy)phenyl-2,4-pyrimidinediamine;II-44:N4-(3-cyclopropylsulfonylaminomethyl)phenyl-N2-(3,5-dimethyl-4-methoxy)phenyl-5-methyl-2,4-pyrimidinediamine;II-45:5-Chloro-N4[4-(N-cyclopropylsulfonylamino)ethylphenyl]-N2-[4-phenyltrifluoromethylsulfone]-2,4-pyrimidinediamine; II-46:5-Chloro-N4[4-(N-cyclopropylsulfonylamino)ethylphenyl]-N2-[4-(2,6-dimethyl-methoxy)phenyl]-2,4-pyrimidinediamine;II-47:5-Chloro-N4[4-(N-cyclopropylsulfonylamino)ethylphenyl]-N2-[4-(2,6-dimethyl-ethoxy)phenyl]-2,4-pyrimidinediamine;II-48:5-Chloro-N4[4-(N-cyclopropylsulfonylamino)ethylphenyl]-N2-[4-(2,6-dimethyl-isopropoxy)phenyl]-2,4-pyrimidinediamine;II-49:5-Chloro-N4[4-(N-cyclopropylsulfonylamino)ethylphenyl]-N2-[4-(2,6-dimethyl-ethoxymorphlino)phenyl]-2,4-pyrimidinediamine);II-50:5-Chloro-N4[4-(N-cyclopropylsulfonylamino)ethylphenyl]-N2-[4-(6-methoxy-2-methyl-methoxy)phenyl]-2,4-pyrimidinediamine;II-51:5-Chloro-N4[4-(N-cyclopropylsulfonylamino)ethylphenyl]-N2-[4-(4-methylpiperazino)phenyl]-2,4-pyrimidinediamine;II-52:5-Chloro-N4[4-(N-cyclopropylsulfonylamino)ethylphenyl]-N2-[4-(4-methylpiperazino)-2-methylphenyl]-2,4-pyrimidinediamine;II-53:5-Chloro-N4[4-(N-cyclopropylsulfonylamino)ethylphenyl]-N2-[4-(4-methylpiperazino)pyrido]-2,4-pyrimidinediamine;II-54:5-Chloro-N4[4-(N-cyclopropylsulfonylamino)ethylphenyl]-N2-[4-(4-propylpiperazino)-2-trifluoromethylphenyl]-2,4-pyrimidinediamine;II-55:5-Chloro-N4[4-(N-cyclopropylsulfonylamino)ethylphenyl]-N2-[4-(4-methylsulfonylpiperazino)-2-trifluoromethylphenyl]-2,4-pyrimidinediamine;II-56:5-Chloro-N4[4-(N-cyclopropylsulfonylamino)ethylphenyl]-N2-[4-(4-methylpiperazino)-2-fluorophenyl]-2,4-pyrimidinediamine;II-57:5-Chloro-N4[4-(N-cyclopropylsulfonylamino)ethylphenyl]-N2-[4-(4-ethylpiperazino)-2-trifluoromethylphenyl]-2,4-pyrimidinediamine;II-58:5-Chloro-N4[4-(N-cyclopropylsulfonylamino)ethylphenyl]-N2-[4-biphenyl]-2,4-pyrimidinediamine;II-59:N4-[4-(N-cyclopropylsulfonylamino)ethylphenyl)]-5-methyl-N2-[4-trifluoromethylsulfonylphenyl]-2,4-pyrimidinediamine; II-60:N-(4-(2-(4-(4-(bicyclo[2.2.1]heptan-2-yl)piperazin-1-yl)phenylamino)-5-methylpyrimidin-4-ylamino)benzyl)cyclopropanesulfonamide;II-61:N-(4-(2-(4-(4-(bicyclo[2.2.1]heptan-2-yl)piperazin-1-yl)phenylamino)-5-chloropyrimidin-4-ylamino)benzyl)cyclopropanesulfonamide;II-62:N4-[4-(N-cyclopropylsulfonylamino)ethylphenyl)]-5-methyl-N2-[4-(2,6-dimethyl)methoxyphenyl]-2,4-pyrimidinediamine;II-63:N4-[4-(N-cyclopropylsulfonylamino)ethylphenyl)]-5-methyl-N2-[4-(2,6-dimethyl)ethoxyphenyl]-2,4-pyrimidinediamine;II-64:N4-[4-(N-cyclopropylsulfonylamino)ethylphenyl)]-5-methyl-N2-[4-(2,6-dimethyl)isopropoxyphenyl]-2,4-pyrimidinediamine; II-65:N4-[4-(N-cyclopropylsulfonylamino)ethylphenyl)]-5-methyl-N2-[4-(2,6-dimethyl)ethoxymorpholino-phenyl]-2,4-pyrimidinediamine;II-66:N4-[4-(N-cyclopropylsulfonylamino)ethylphenyl)]-5-methyl-N2-[4-(6-methoxy-2-methyl)methoxyphenyl]-2,4-pyrimidinediamine;II-67:N4-[4-(N-cyclopropylsulfonylamino)ethylphenyl)]-5-methyl-N2-[4-(4-methylpiperazino)phenyl]-2,4-pyrimidinediamine;II-68:N4-[4-(N-cyclopropylsulfonylamino)ethylphenyl)]-5-methyl-N2-[4-(4-methylpiperazino)-2-methylphenyl]-2,4-pyrimidinediamine;II-69:N4-[4-(N-cyclopropylsulfonylamino)ethylphenyl)]-5-methyl-N2-[4-(4-methylpiperazino)pyrido]-2,4-pyrimidinediamine;II-70:N4-[4-(N-cyclopropylsulfonylamino)ethylphenyl)]-5-methyl-N2-[4-(4-methylpiperazino)-2-trifluoromethylphenyl]-2,4-pyrimidinediamine;II-71:N4-[4-(N-cyclopropylsulfonylamino)ethylphenyl)]-5-methyl-N2-[4-(4-propylpiperazino)-2-trifluoromethylphenyl]-2,4-pyrimidinediamine;II-72:N4-[4-(N-cyclopropylsulfonylamino)ethylphenyl)]-5-methyl-N2-[4-(4-sulfonylmethyl-piperazino)-2-trifluoromethylphenyl]-2,4-pyrimidinediamine;II-73:N4-[4-(N-cyclopropylsulfonylamino)ethylphenyl)]-5-methyl-N2-[4-(4-methylpiperazino)-2-fluorophenyl]-2,4-pyrimidinediamine;II-74:N4-[4-(N-cyclopropylsulfonylamino)ethylphenyl)]-5-methyl-N2-[4-(4-ethylpiperazino)-2-trifluoromethylphenyl]-2,4-pyrimidinediamine;II-75:N4-[4-(N-cyclopropylsulfonylamino)ethylphenyl)]-5-methyl-N2-[4-biphenyl]-2,4-pyrimidinediamine;II-76:N-(3-(2-(4-(4-(bicyclo[2.2.1]heptan-2-yl)piperazin-1-yl)phenylamino)-5-chloropyrimidin-4-ylamino)-5-methylbenzyl)cyclopropanesulfonamide;II-77:N-(3-(2-(4-(4-(bicyclo[2.2.1]heptan-2-yl)piperazin-1-yl)phenylamino)-5-methylpyrimidin-4-ylamino)-5-methylbenzyl)cyclopropanesulfonamide;II-78:N-(4-(2-(4-(4-(bicyclo[2.2.1]heptan-2-yl)piperazin-1-yl)-3-fluorophenylamino)-5-methylpyrimidin-4-ylamino)benzyl)cyclopropanesulfonamide;II-79:N-(4-(2-(4-(4-(bicyclo[2.2.1]heptan-2-yl)piperazin-1-yl)-3-fluorophenylamino)-5-chloropyrimidin-4-ylamino)benzyl)cyclopropanesulfonamide;II-80:5-Chloro-N2-(3-chloro-4-methoxy-5-methylphenyl]-N4-[4-(N-cyclopropylsulfonylamino)methylphenyl]-2,4-pyrimidinediamine;II-81:N4-[4-(N-Cyclopropylsulfonylamino)methylphenyl]-N2-(3,5-dimethyl-4-methoxyphenyl)-5-ethyl-2,4-pyrimidinediamine;II-82:N4-[4-(N-Cyclopropylsulfonylamino)methylphenyl]-N2-(3,4-dimethoxy-5-methylphenyl)-5-ethyl-2,4-pyrimidinediamine;II-83:N2-(3-Chloro-4-methoxy-5-methylphenyl)-N4-[4-(N-cyclopropylsulfonylamino)methylphenyl]-5-ethyl-2,4-pyrimidinediamine;II-84:N4-[4-(N-Cyclopropylsulfonylamino)methylphenyl]-N2-(3,5-dichloro-4-methoxyphenyl)-5-ethyl-2,4-pyrimidinediamine;II-85:N4-[4-(N-Cyclopropylsulfonylamino)methylphenyl]-5-ethyl-N2-(3-,4,5-trimethoxylphenyl)-2,4-pyrimidinediamine;II-86:N4-[4-(N-Cyclopropylsulfonylamino)methylphenyl]-5-ethyl-N2-[4-(4-methyl-1-piperazinyl)phenyl]-2,4-pyrimidinediamine;II-87:N4-[4-(N-Cyclopropylsulfonylamino)methylphenyl]-N2-[4-(4,4-difluoro-1-piperidinyl)phenyl]-5-ethyl-2,4-pyrimidinediamine;II-88:N4-[4-(N-Cyclopropylsulfonylamino)methylphenyl]-5-ethyl-N2-[4-(1-methyl-4-piperidinyl)pheny]-2,4-pyrimidinediamine;II-89:N4-[4-(N-Cyclopropylsulfonylamino)methylphenyl]-5-ethyl-N2-[4-(4-ethyl-1-piperazinyl)phenyl]-2,4-pyrimidinediamine;II-90:5-Chloro-N2-(3,5-dimethyl-5-methoxyphenyl)-N4-[(4-(dimethylamino)sulfonylamino)methylphenyl]-2,4-pyrimidinediamine;II-91:5-Chloro-N2-(3,4-dimethoxy-5-methylphenyl)-N4-[(4-(dimethylamino)sulfonylamino)methylphenyl]-2,4-pyrimidinediamine;II-92:5-Chloro-N2-(3-chloro-4,5-dimethoxyphenyl)-N4-[(4-(dimethylamino)sulfonylamino)methylphenyl]-2,4-pyrimidinediamine;II-93:5-Chloro-N2-(3-chloro-4-methoxy-5-methylphenyl)-N4-[(4-(dimethylamino)sulfonylamino)methylphenyl]-2,4-pyrimidinediamine;II-94:5-Chloro-N2-[3,5-dichloro-4-methoxyphenyl]-N4-[(4-(dimethylamino)sulfonylamino)methylphenyl]-2,4-pyrimidinediamine;II-95:5-Chloro-N4-[(4-(dimethylamino)sulfonylamino)methylphenyl]-N2-[3,4,5-trimethoxyphenyl)-2,4-pyrimidinediamine;II-96:5-Chloro-N4-[(4-(dimethylamino)sulfonylamino)methylphenyl]-N2-[4-(4-methyl-1-piperazinyl)phenyl]-2,4-pyrimidinediamine;II-97:5-Chloro-N4-[(4-(dimethylamino)sulfonylamino)methylphenyl]-N2-[4-(4,4-difluoro-1-piperidinyl)phenyl]-2,4-pyrimidinediamine;II-98:5-Chloro-N4-[(4-(dimethylamino)sulfonylamino)methylphenyl]-N2-[4-(1-methyl-4-piperidinyl)pheny]-2,4-pyrimidinediamine;II-99:4-[(4-(Dimethylamino)sulfonylamino)methylphenyl]-N2-(3,5-dimethyl-4-methoxyphenyl)-5-methyl-2,4-pyrimidinediamine;II-100:4-[(4-(Dimethylamino)sulfonylamino)methylphenyl]-N2-(3,4-dimethoxy-5-methylphenyl)-5-methyl-2,4-pyrimidinediamine;II-101:5-Methyl-N2-(3-chloro-4-methoxy-5-methylphenyl)-N4-[(4-(dimethylamino)sulfonylamino)methylphenyl]-2,4-pyrimidinediamine;II-102:5-methyl-N2-[3,5-dichloro-4-methoxyphenyl]-N4-[(4-(dimethylamino)sulfonylamino)methylphenyl]-2,4-pyrimidinediamine;II-103:N4-[(4-(Dimethylamino)sulfonylamino)methylphenyl]-5-methyl-N2-(3,4,5-trimethoxyphenyl)-2,4-pyrimidinediamine;II-104:N4-[(4-(Dimethylamino)sulfonylamino)methylphenyl]-5-methyl-N2-[4-(4-methyl-1-piperazinyl)phenyl]-2,4-pyrimidinediamine;II-105:N4-[(4-(Dimethylamino)sulfonylamino)methylphenyl]-N2-[4-(4,4-difluoro-1-piperidinyl)phenyl]-5-methyl-2,4-pyrimidinediamine;II-106:N4-[(4-(Dimethylamino)sulfonylamino)methylphenyl]-5-methyl-N2-[4-(1-methyl-4-piperidinyl)phenyl]-2,4-pyrimidinediamine;II-107:N4-[(4-(Dimethylamino)sulfonylamino)methylphenyl]-5-methyl-N2-[4-(4-ethyl-1-piperazinyl)phenyl]-2,4-pyrimidinediamine;II-108:5-chloro-N2-(3,5-Dimethyl-4-methoxyphenyl)-N4-[(4-(ethylamino)sulfonylamino)methylphenyl]-2,4-pyrimidinediamine;II-109:5-Chloro-4-[(4-(ethylamino)sulfonylamino)methylphenyl]-N2-(3,4-dimethoxy-5-methylphenyl)-2,4-pyrimidinediamine;II-110:5-Chloro-N2-(3-chloro-4-methoxy-5-methylphenyl)-N4-[(4-(ethylamino)sulfonylamino)methylphenyl]-2,4-pyrimidinediamine;II-111:5-Chloro-N2-[3,5-dichloro-4-methoxyphenyl]-N4-[(4-(ethylamino)sulfonylamino)methylphenyl]-2,4-pyrimidinediamine;II-112:5-Chloro-N4-[(4-(ethylamino)sulfonylamino)methylphenyl]-N2-(3,4,5-trimethoxyphenyl)-2,4-pyrimidinediamine;II-113:5-Chloro-N2-(3-chloro-4,5-dimethoxyphenyl)-N4-[(4-(ethylamino)sulfonylamino)methylphenyl]-2,4-pyrimidinediamine;II-114:5-Chloro-N4-[(4-(ethylamino)sulfonylamino)methylphenyl]-N2-[4-(4-methyl-1-piperazinyl)phenyl]-2,4-pyrimidinediamine;II-115:5-chloro-N4-[(4-(ethylamino)sulfonylamino)methylphenyl]-N2-[4-(1-methyl-4-piperidinyl)phenyl]-2,4-pyrimidinediamine;II-116:N2-(3,5-Dimethyl-4-methoxyphenyl)-N4-[(4-(ethylamino)sulfonylamino)methylphenyl]-5-methyl-2,4-pyrimidinediamine;II-117:N2-(3,4-Dimethoxy-5-methylphenyl)-N4-[(4-(ethylamino)sulfonylamino)methylphenyl]-5-methyl-2,4-pyrimidinediamine;II-118:N2-(3-Chloro-4-methoxy-5-methylphenyl)-N4-[(4-(ethylamino)sulfonylamino)methylphenyl]-5-methyl-2,4-pyrimidinediamine;II-119:N2-[3,5-Dichloro-4-methoxyphenyl]-N4-[(4-(ethylamino)sulfonylamino)methylphenyl]-5-methyl-2,4-pyrimidinediamine;II-120:N4-[(4-(Ethylamino)sulfonylamino)methylphenyl]-5-methyl-N2-(3,4,5-trimethoxyphenyl)-2,4-pyrimidinediamine;II-121:N2-(3-Chloro-4,5-dimethoxyphenyl)-N4-[(4-(ethylamino)sulfonylamino)methylphenyl]-5-methyl-2,4-pyrimidinediamine;II-122:N4-[(4-(Ethylamino)sulfonylamino)methylphenyl]-5-methyl-N2-[4-(4-methyl-1-piperazinyl)phenyl]-2,4-pyrimidinediamine;II-123:N2-[4-(4,4-Difluoro-1-piperidinyl)phenyl]-N4-[(4-(ethylamino)sulfonylamino)methylphenyl]-5-methyl-2,4-pyrimidinediamine;II-124:N4-[(4-(Ethylamino)sulfonylamino)methylphenyl]-5-methyl-N2-[4-(1-methyl-4-piperidinyl)phenyl]-2,4-pyrimidinediamine;II-125:N4-[(4-(ethylamino)sulfonylamino)methylphenyl]-N2-[4-(4-ethyl-1-piperazinyl)phenyl]-5-methyl-2,4-pyrimidinediamine;II-126:N4-[4-(N-Cyclopropylsulfonylamino)methylphenyl]-N2-(3,5-dimethyl-4-methoxyphenyl)-5-trifluoromethyl-2,4-pyrimidinediamine;II-127:N4-[4-(N-Cyclopropylsulfonylamino)methylphenyl]-N2-[4-(4-methyl-1-piperazinyl)phenyl]-5-trifluoromethyl-2,4-pyrimidinediamine;II-128:N4-[4-(N-Cyclopropylsulfonylamino)methylphenyl]-N2-[3-methyl-4-(4-methyl-1-piperazinyl)phenyl]-5-trifluoromethyl-2,4-pyrimidinediamine;II-129:5-Chloro-N2-(3,5-dimethyl-4-methoxyphenyl)-N4-[(3-(ethylamino)sulfonylamino)methylphenyl]-2,4-pyrimidinediamine;II-130:5-Chloro-N2-(3,5-dimethyl-4-ethoxyphenyl)-N4-[(3-(ethylamino)sulfonylamino)methylphenyl]-2,4-pyrimidinediamine;II-131:5-Chloro-N4-[(3-(ethylamino)sulfonylamino)methylphenyl]-N2-[4-(4-methyl-1-piperazinyl)phenyl]-2,4-pyrimidinediamine;II-132:5-Chloro-N4-[(3-(ethylamino)sulfonylamino)methylphenyl]-N2-[3-methyl-4-(4-methyl-1-piperazinyl)phenyl]-2,4-pyrimidinediamine;II-133:N2-(3,5-Dimethyl-4-methoxyphenyl)-N4-[(3-(ethylamino)sulfonylamino)methylphenyl]-5-methyl-2,4-pyrimidinediamine;II-134:N2-(3,5-Dimethyl-4-ethoxyphenyl)-N4-[(3-(ethylamino)sulfonylamino)methylphenyl]-5-methyl-2,4-pyrimidinediamine;II-135:N4-[(3-(Ethylamino)sulfonylamino)methylphenyl]-5-methyl-N2-[4-(4-methyl-1-piperazinyl)phenyl]-2,4-pyrimidinediamine;II-136:N4-[3-((Ethylamino)sulfonylamino)methylphenyl]-5-methyl-N2-[3-methyl-4-(4-methyl-1-piperazinyl)phenyl]-2,4-pyrimidinediamine;II-137:N2-(3,5-Dimethyl-4-methoxyphenyl)-N4-[(3-(ethylamino)sulfonylamino)methylphenyl]-5-fluoro-2,4-pyrimidinediamine;II-138:N4-[3-((Ethylamino)sulfonylamino)methylphenyl]-5-fluoro-N2-[4-(4-methyl-1-piperazinyl)phenyl]-2,4-pyrimidinediamine;II-139:N4-[3-((Ethylamino)sulfonylamino)methylphenyl]-5-fluoro-N2-[3-methyl-4-(4-methyl-1-piperazinyl)phenyl]-2,4-pyrimidinediamine;II-140:5-Chloro-N4-[4-[N-(Cyclopropylsulfonyl)-N′-((3-ethoxycarbonyl)propion-1-yl)amino]methylphenyl]-N2-(3,5-dimethyl-4-methoxyphenyl)-2,4-pyrimidinediamine;II-141:5-Chloro-N4-[4-[N-cyclopropylsulfonyl)-N′-(3-(4-morpholine)propion-1-yl)amino]methylphenyl]-N2-(3,5-dimethyl-4-methoxyphenyl)-2,4-pyrimidinediamine;II-142:5-Chloro-N2-(3,5-dimethyl-4-methoxyphenyl)-N4-[2-methyl-4-(ethylaminosulfonylamino)methylphenyl]-2,4-pyrimidinediamine;II-143:5-Chloro-N2-(3,5-dimethyl-4-ethoxyphenyl)-N4-[2-methyl-4-(ethylaminosulfonylamino)methylphenyl]-2,4-pyrimidinediamine;II-144:5-Chloro-N4-[2-methyl-4-(ethylaminosulfonylamino)methylphenyl]-N2-[4-(4-methyl-1-piperazinyl)phenyl]-2,4-pyrimidinediamine;II-145:5-Chloro-N4-[2-methyl-4-(ethylaminosulfonylamino)methylphenyl]-N2-[3-methyl-4-(4-methyl-1-piperazinyl)phenyl]-2,4-pyrimidinediamine;II-146:N4-[4-(Aminosulfonylamino)methylphenyl]-5-chloro-N2-(3,5-dimethyl-4-methoxyphenyl)-2,4-pyrimidinediamine;II-147:N4-[4-(Aminosulfonylamino)methylphenyl]-5-chloro-N2-(3,5-Dimethyl-4-ethoxyphenyl)-2,4-pyrimidinediamine;II-148:N4-[4-(Aminosulfonylamino)methylphenyl]-5-chloro-N2-[4-(4-methyl-1-piperazinyl)phenyl]-2,4-pyrimidinediamine;II-149:N4-[4-(Aminosulfonylamino)methylphenyl]-5-chloro-N2-[3-methyl-4-(4-methyl-1-piperazinyl)phenyl]-2,4-pyrimidinediamine;II-150:5-Chloro-N2-(3,5-dimethyl-4-methoxyphenyl)-N4-[2-methyl-4-(N-cyclopropylsulfonylamino)methylphenyl]-2,4-pyrimidinediamine;II-151:5-Chloro-N2-(3,5-dimethyl-4-ethoxyphenyl)-N4-[2-methyl-4-(N-cyclopropylsulfonylamino)methylphenyl]-2,4-pyrimidinediamine;II-152:5-Chloro-N4-[2-methyl-4-(N-cyclopropylsulfonylamino)methylphenyl]-N2-[4-(4-methyl-1-piperazinyl)phenyl]-2,4-pyrimidinediamine;II-153:5-Chloro-N4-[2-methyl-4-(N-cyclopropylsulfonylamino)methylphenyl]-N2-[3-methyl-4-(4-methyl-1-piperazinyl)phenyl]-2,4-pyrimidinediamine;II-154:5-Chloro-N4-[4-((N-cyclopropylamino)sulfonylamino)methylphenyl]-N2-(3,5-dimethyl-4-methoxyphenyl)-2,4-pyrimidinediamine;II-155:5-Chloro-N4-[4-((N-cyclopropylamino)sulfonylamino)methylphenyl]-N2-(3,5-dimethyl-4-ethoxyphenyl)-2,4-pyrimidinediamine;II-156:5-Chloro-N4-[4-((N-cyclopropylamino)sulfonylamino)methylphenyl]-N2-(3,5-dimethyl-4-(1-methyl)ethoxyphenyl)-2,4-pyrimidinediamine;II-157:5-Chloro-N4-[4-((N-cyclopropylamino)sulfonylamino)methylphenyl]-N2-(3,5-dimethyl-4-propoxyphenyl)-2,4-pyrimidinediamine;II-158:5-Chloro-N4-[4-((N-cyclopropylamino)sulfonylamino)methylphenyl]-N2-(3,4-dimethoxy-5-methylphenyl)-2,4-pyrimidinediamine;II-159:N4-[4-(N-Cyclopropylsulfonylamino)methylphenyl]-N2-[3,4-dimethyl-4-(2-(4-morpholinyl)ethoxy)phenyl]-5-methyl-2,4-pyrimidinediamine;II-160:5-Chloro-N4-[4-(N-cyclopropylsulfonylamino)methylphenyl]-N2-[3,4-dimethyl-4-(2-(4-morpholinyl)ethoxy)phenyl]-2,4-pyrimidinediamine;II-161:N2-[3,4-Dimethyl-4-(2-(4-morpholinyl)ethoxy)phenyl]-5-methyl-N4-[2-methyl-4-(N-cyclopropylsulfonylamino)methylphenyl]-2,4-pyrimidinediamine;II-162:N4-[4-((N-Cyclopropylamino)sulfonylamino)methylphenyl]-N2-(3,5-dimethyl-4-methoxyphenyl)-5-methyl-2,4-pyrimidinediamine;II-163:N4-[4-((N-Cyclopropylamino)sulfonylamino)methylphenyl]-N2-(3,5-dimethyl-4-ethoxyphenyl)-5-methyl-2,4-pyrimidinediamine;II-164:N4-[4-((N-Cyclopropylamino)sulfonylamino)methylphenyl]-N2-[3,5-dimethyl-4-(1-methyl)ethoxyphenyl]-5-methyl-2,4-pyrimidinediamine;II-165:N4-[4-((N-Cyclopropylamino)sulfonylamino)methylphenyl]-N2-(3,5-dimethyl-4-propoxyphenyl)-5-Methyl-2,4-pyrimidinediamine;II-166:N4-[4-((N-Cyclopropylamino)sulfonylamino)methylphenyl]-N2-(3,4-dimethoxy-5-methylphenyl)-5-methyl-2,4-pyrimidinediamine;II-167:5-Chloro-N4-[4-((N-cyclopropylamino)sulfonylamino)methylphenyl]-N2-[4-(4-methyl-1-piperazinyl)phenyl]-2,4-pyrimidinediamine;II-168:5-Chloro-N4-[4-((N-cyclopropylamino)sulfonylamino)methylphenyl]-N2-[3-methyl-4-(4-methyl-1-piperazinyl)phenyl]-2,4-pyrimidinediamine;II-169:5-Chloro-N4-[4-((N-cyclopropylamino)sulfonylamino)methylphenyl]-N2-[6-(4-methyl-1-piperazinyl)-3-pyridinyl]-2,4-pyrimidinediamine;II-170:5-Chloro-N2-[3,4-dimethyl-4-(2-(4-morpholinyl)ethoxy)phenyl]-N4-[4-((N-cyclopropylamino)sulfonylamino)methylphenyl]-2,4-pyrimidinediamine;II-171:N4-[4-((N-Cyclopropylamino)sulfonylamino)methylphenyl]-5-methyl-N2-[4-(4-methyl-1-piperazinyl)phenyl]-2,4-pyrimidinediamine;II-172:N4-[4-((N-Cyclopropylamino)sulfonylamino)methylphenyl]-5-methyl-N2-[3-methyl-4-(4-methyl-1-piperazinyl)phenyl]-2,4-pyrimidinediamine;II-173:N4-[4-((N-Cyclopropylamino)sulfonylamino)methylphenyl]-5-methyl-N2-[6-(4-methyl-1-piperazinyl)-3-pyridinyl]-2,4-pyrimidinediamine;II-174:N2-[3,4-Dimethyl-4-(2-(4-morpholinyl)ethoxy)phenyl]-N4-[4-((N-cyclopropylamino)sulfonylamino)methylphenyl]-5-methyl-2,4-pyrimidinediamine;II-175:5-Chloro-N2-(3,5-dimethyl-4-methoxyphenyl)-N4-[2-methyl-4-((N-cyclopropylamino)sulfonylamino)methylphenyl]-2,4-pyrimidinediamine;II-176:5-Chloro-N2-(3,5-dimethyl-4-ethoxyphenyl)-N4-[2-methyl-4-((N-cyclopropylamino)sulfonylamino)methylphenyl]-2,4-pyrimidinediamine;II-177:5-Chloro-N2-(3,5-dimethyl-4-(1-methylethoxy)phenyl)-N4-[2-methyl-4-((N-cyclopropylamino)sulfonylamino)methylphenyl]-2,4-pyrimidinediamine;II-178:5-Chloro-N2-(3,5-dimethyl-4-propoxyphenyl)-N4-[2-methyl-4-((N-cyclopropylamino)sulfonylamino)methylphenyl]-2,4-pyrimidinediamine;II-179:5-Chloro-N2-(3,4-dimethoxy-5-methylphenyl)-N4-[2-methyl-4-((N-cyclopropylamino)sulfonylamino)methylphenyl]-2,4-pyrimidinediamine;II-180:5-Chloro-N4-[2-methyl-4-((N-cyclopropylamino)sulfonylamino)methylphenyl]-N2-[4-(4-methyl-1-piperazinyl)phenyl]-2,4-pyrimidinediamine;II-181:5-Chloro-N4-[2-methyl-4-((N-cyclopropylamino)sulfonylamino)methylphenyl]-N2-[3-methyl-4-(4-methyl-1-piperazinyl)phenyl]-2,4-pyrimidinediamine;II-182:5-Chloro-N4-[2-methyl-4-((N-cyclopropylamino)sulfonylamino)methylphenyl]-N2-[6-(4-methyl-1-piperazinyl)-3-pyridinyl]-2,4-pyrimidinediamine;II-183:5-Chloro-N2-[3,4-dimethyl-4-(2-(4-morpholinyl)ethoxy)phenyl]-N4-[2-methyl-4-((N-cyclopropylamino)sulfonylamino)methylphenyl]-2,4-pyrimidinediamine;II-184:N4-[4-(N-Cyclopropylsulfonylamino)methylphenyl]-5-methyl-N2-[3-methyl-4-[(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]phenyl]-2,4-pyrimidinediamine;II-185:5-Chloro-N4-[4-(N-Cyclopropylsulfonylamino)methylphenyl]-N2-[3-methyl-4-[(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]phenyl]-2,4-pyrimidinediamine;II-186:5-Chloro-N4-[4-(N-cyclopropylsulfonylaminomethyl)phenyl]-N2-[3,4,5-trimethoxyphenyl]-2,4-pyrimidinediamine;II-187:5-Chloro-N4-[4-(N-cyclopropylsulfonylaminomethyl)phenyl]-N2-[4-(N-methylpiperidin-4-yl)phenyl]-2,4-pyrimidinediamine;II-188:5-Chloro-N4-[4-(N-cyclopropylsulfonylamino)methylphenyl]-N2-[4-(N-methylpiperizin-4-yl)phenyl]-2,4-pyrimidinediamine;II-189:5-Chloro-N4-[3-(N-cyclopropylsulfonylamino)methylphenyl]-N2-[3,4,5-trimethoxyphenyl]-2,4-pyrimidinediamine;II-190:5-Chloro-N4-[3-(N-cyclopropylsulfonylaminomethyl)phenyl]-N2-[4-(N-methylpiperidin-4-yl)phenyl]-2,4-pyrimidinediamine;II-191:5-Chloro-N4-[3-(N-cyclopropylsulfonylamino)methylphenyl]-N2-[4-(N-methylpiperizin-4-yl)phenyl]-2,4-pyrimidinediamine;II-192:5-Chloro-N4-[3-(N-cyclopropylsulfonylamino)methylphenyl]-N2-[3,5-dimethyl-4-methoxyphenyl]-2,4-pyrimidinediamine;II-193:5-Chloro-N4-[4-(N-cyclopropylsulfonylamino)methylphenyl]-N2-[4-(3-pyridinyl)phenyl]-2,4-pyrimidinediamine;II-194:5-Chloro-N4-[3-(N-cyclopropylsulfonylamino)methylphenyl]-N2-[4-(3-pyridinyl)phenyl]-2,4-pyrimidinediamine;II-195:5-Fluoro-N4-[4-(N-cyclopropylsulfonylamino)methylphenyl]-N2-[3,4-dimethoxy-5-methylphenyl]-2,4-pyrimidinediamineII-196:5-Fluoro-N4-[4-(N-cyclopropylsulfonylamino)methylphenyl]-N2-[3,4-dimethoxy-5-chlorophenyl]-2,4-pyrimidinediamine;II-197:5-Methyl-N4-[4-(N-cyclopropylsulfonylamino)methylphenyl]-N2-[3,4-dimethoxy-5-methylphenyl]-2,4-pyrimidinediamine;II-198:5-Methyl-N4-[4-(N-cyclopropylsulfonylamino)methylphenyl]-N2-[3,4-dimethoxy-5-chlorophenyl]-2,4-pyrimidinediamine;II-199:5-Chloro-N4-[4-(N-cyclopropylsulfonylamino)methylphenyl]-N2-[3,4-dimethoxy-5-methylphenyl]-2,4-pyrimidinediamine;II-200:5-Chloro-N4-[4-(N-cyclopropylsulfonylamino)methylphenyl]-N2-[3,4-dimethoxy-5-chlorophenyl]-2,4-pyrimidinediamine;II-201:5-Methyl-N4-[4-(N-cyclopropylsulfonylamino)methylphenyl]-N2-[3,5-dimethyl-4-methoxyphenyl]-2,4-pyrimidinediamine;II-202:5-Methyl-N4-[4-(N-cyclopropylsulfonylamino)methylphenyl]-N2-[3-methyl-4-(N-methylpiperizin-4-yl)phenyl]-2,4-pyrimidinediamine;II-203:5-Chloro-N4-[4-(N-cyclopropylsulfonylamino)methylphenyl]-N2-[3-methyl-4-(N-methylpiperizin-4-yl)phenyl]-2,4-pyrimidinediamine;II-204:5-Methyl-N4-[4-(N-cyclopropylsulfonylamino)methylphenyl]-N2-[4-(N-ethylpiperizin-4-yl)phenyl]-2,4-pyrimidinediamine;II-205:5-Chloro-N4-[4-(N-cyclopropylsulfonylamino)methylphenyl]-N2-[4-(N-ethylpiperizin-4-yl)phenyl]-2,4-pyrimidinediamine;II-206:5-Methyl-N4-[4-(N-cyclopropylsulfonylamino)methylphenyl]-N2-[4-[N-(methansulfonyl)piperizin-4-ylphenyl]-2,4-pyrimidinediamine;II-207:5-Chloro-N4-[4-(N-cyclopropylsulfonylamino)methylphenyl]-N2-[4-[N-(methansulfonyl)piperizin-4-ylphenyl]-2,4-pyrimidinediamine;II-208:5-chloro-N2-(3-Methyl-4,5-dimethoxyphenyl)-N4-[(4-(ethylamino)sulfonylamino)methylphenyl]-2,4-pyrimidinediamine;II-209:5-Methyl-N4-[4-(N-cyclopropylsulfonylamino)methylphenyl]-N2-[3,4-dimethoxy-5-ethoxyphenyl]-2,4-pyrimidinediamine;II-210:5-Chloro-N4-[4-(N-cyclopropylsulfonylamino)methylphenyl]-N2-[3,4-dimethoxy-5-ethoxyphenyl]-2,4-pyrimidinediamine;II-211:5-Chloro-N4-[4-(N-cyclopropylsulfonylamino)methylphenyl]-N2-[3,5-dimethyl-4-ethoxyphenyl]-2,4-pyrimidinediamine;II-212:5-Methyl-N4-[4-(N-cyclopropylsulfonylamino)methylphenyl]-N2-[2,4-dimethyl-5-chlorophenyl]-2,4-pyrimidinediamine;II-213:5-Chloro-N4-[4-(N-cyclopropylsulfonylamino)methylphenyl]-N2-[2,4-dimethyl-5-chlorophenyl]-2,4-pyrimidinediamine;II-214:5-Methyl-N4-[4-(N-cyclopropylsulfonylamino)methylphenyl]-N2-[3,5-dimethyl-4-ethoxyphenyl]-2,4-pyrimidinediamine;II-215:5-Methyl-N4-[4-(N-cyclopropylsulfonylamino)methylphenyl]-N2-[4-(N-methylpiperizin-4-yl)pyridine-3-yl]-2,4-pyrimidinediamine;II-216:5-Chloro-N4-[4-(N-cyclopropylsulfonylamino)methylphenyl]-N2-[4-(N-methylpiperizin-4-yl)pyridine-3-yl]-2,4-pyrimidinediamine;II-217:5-Chloro-N4-[4-(N-cyclopropyl-N-acetylsulfonylamino)methylphenyl]-N2-[3,4-dimethyl-5-methoxyphenyl]-2,4-pyrimidinediamine;II-218:5-Chloro-N4-[4-(N-cyclopropyl-N-propionylsulfonylamino)methylphenyl]-N2-[3,5-dimethyl-4-methoxyphenyl]-2,4-pyrimidinediamine;II-219:5-Methyl-N4-[4-(N-cyclopropylsulfonylamino)methylphenyl]-N2-[3,5-dimethyl-4-(2-propoxy)phenyl]-2,4-pyrimidinediamine;II-220:5-Chloro-N4-[4-(N-cyclopropylsulfonylamino)methylphenyl]-N2-[3,5-dimethyl-4-(2-propoxy)phenyl]-2,4-pyrimidinediamine;II-221:5-Chloro-N4-[4-(N-cyclopropylsulfonylamino)methylphenyl]-N2-[3,5-dimethyl-4-(1-propoxy)phenyl]-2,4-pyrimidinediamine;II-222:5-Methyl-N4-[4-(N-cyclopropylsulfonylamino)methylphenyl]-N2-[4-(1-morpholinomethyl)phenyl]-2,4-pyrimidinediamine;II-223:5-Chloro-N4-[4-(N-cyclopropylsulfonylamino)methylphenyl]-N2-[4-(1-morpholinomethyl)phenyl]-2,4-pyrimidinediamine;II-224:5-Methyl-N4-[4-(N-cyclopropylsulfonylamino)methylphenyl]-N2-[5-methyl-4-(N-methylpiperizin-4-yl)pyridin-3-yl]-2,4-pyrimidinediamine;II-225:5-Chloro-N4-[4-(N-cyclopropylsulfonylamino)methylphenyl]-N2-[5-methyl-4-(N-methylpiperizin-4-yl)pyridin-3-yl]-2,4-pyrimidinediamine;III-1:N4-[4-(Cyclopropylsulfonylaminomethyl)phenyl]-5-fluoro-N2-[1-(2-(N-morpholino)ethyl)indol-6-yl]-2,4-pyrimidinediamine;III-2:N4-[4-(Cyclopropylsulfonylaminomethyl)phenyl]-5-fluoro-N2-[1-(2-(N-morpholino)ethylaminocarbonyl)indol-6-yl]-2,4-pyrimidinediamine;III-3:N4-(4-cyclopropylsulfonylaminomethyl)phenyl-5-methyl-N2-(2-methylbenzoimidazol-5-yl)-2,4-pyrimidinediamine;III-4:N4-(3-cyclopropylsulfonylaminomethyl)phenyl-5-methyl-N2-(2-methylbenzoimidazol-5-yl)-2,4-pyrimidinediamine;III-5:N4-(4-cyclopropylsulfonylaminomethyl)phenyl-5-fluoro-N2-(2-methylbenzoimidazol-5-yl)-2,4-pyrimidinediamine;III-6:5-chloro-N4-(4-cyclopropylsulfonylaminomethyl)phenyl-N2-(2-methylbenzoimidazol-5-yl)-2,4-pyrimidinediamine;III-7:5-Chloro-N4-[3-(N-cyclopropylsulfonylaminomethyl)phenyl]-N2-[2-methylbenzamidazol-5-yl]-2,4-pyrimidinediamine;IV-1:N2-(benzoimidazol-5-yl)-N4-(4-cyclopropylsulfonylaminomethyl)phenyl-5-methyl-2,4-pyrimidinediamine;IV-2:N4-(4-cyclopropylsulfonylaminomethyl)phenyl-5-methyl-N2-(2-trifluoromethylbenzoimidazol-5-yl)-2,4-pyrimidinediamine;IV-3:N4-(4-cyclopropylsulfonylaminomethyl)phenyl-5-methyl-N2-[2-(pyridin-3-yl)benzoimidazol-5-yl]-2,4-pyrimidinediamine;IV-4:N2-(2-tert-butylbenzoimidazol-5-yl)-N4-(4-cyclopropylsulfonylaminomethyl)phenyl-5-methyl-2,4-pyrimidinediamine;IV-5:N4-(4-cyclopropylsulfonylaminomethyl)phenyl-5-methyl-N2-[2-(thien-2-yl)benzoimidazol-5-yl]-2,4-pyrimidinediamine;IV-6:N4-(4-cyclopropylsulfonylaminomethyl)phenyl-5-methyl-N2-[2-(morpholin-4-yl)methylbenzoimidazol-5-yl]-2,4-pyrimidinediamine;IV-7:N4-(4-cyclopropylsulfonylaminomethyl)phenyl-N2-(1,2-dimethylbenzoimidazol-5-yl)-5-methyl-2,4-pyrimidinediamine;IV-8:N4-(4-cyclopropylsulfonylaminomethyl)phenyl-N2-[1-(2-hydroxyethyl)benzoimidazol-5-yl]-5-methyl-2,4-pyrimidinediamine;IV-9:N4-(3-cyclopropylsulfonylaminomethyl)phenyl-N2-[1-(2-hydroxyethyl)benzoimidazol-5-yl]-5-methyl-2,4-pyrimidinediamine;IV-10:N4-(3-cyclopropylsulfonylaminomethyl)phenyl-N2-(1,2-dimethylbenzoimidazol-5-yl)-5-methyl-2,4-pyrimidinediamine;IV-11:N4-(3-cyclopropylsulfonylaminomethyl)phenyl-5-methyl-N2-[2-(thien-2-yl)benzoimidazol-5-yl]-2,4-pyrimidinediamine;IV-12:N4-(3-cyclopropylsulfonylaminomethyl)phenyl-5-methyl-N2-[2-(pyridin-3-yl)benzoimidazol-5-yl]-2,4-pyrimidinediamine;IV-13:N2-(benzoimidazol-5-yl)-N4-(3-cyclopropylsulfonylaminomethyl)phenyl-5-methyl-2,4-pyrimidinediamine;IV-14:N4-(3-cyclopropylsulfonylaminomethyl)phenyl-5-methyl-N2-(2-trifluoromethylbenzoimidazol-5-yl)-2,4-pyrimidinediamine;IV-15:N2-(2-tert-butylbenzoimidazol-5-yl)-N4-(3-cyclopropylsulfonylaminomethyl)phenyl-5-methyl-2,4-pyrimidinediamine;IV-16:N4-(3-cyclopropylsulfonylaminomethyl)phenyl-5-methyl-N2-[2-(morpholin-4-yl)methylbenzoimidazol-5-yl]-2,4-pyrimidinediamine;V-1:(+/−)-5-Methyl-N4-[1-(methylsulfonylamino)indan-6-yl]-N2-(3,4,5-trimethoxyphenyl)-2,4-pyrimidinediamine;V-2:(+/−)-5-Methyl-N2-[4-(1-methyl-4-piperidinyl)pheny]-N4-[1-(methylsulfonyl)aminoindan-6-yl]-2,4-pyrimidinediamine;V-3:(+/−)-N4-[1-(Cyclopropylsulfonylamino)indan-6-yl]-5-Methyl-N2-(3,4,5-trimethoxyphenyl))-2,4-pyrimidinediamine;V-4:(+/−)-N4-[1-(Cyclopropylsulfonylamino)indan-6-yl]-5-methyl-N2-[4-(4-methyl-1-piperazinyl)phenyl]-2,4-pyrimidinediamine;V-5:(+/−)-N-4-[1-(Cyclopropylsulfonylamino)indan-6-yl]-5-methyl-N2-[4-(1-methyl-4-piperidinyl)pheny]-2,4-pyrimidinediamine;V-6:(+/−)-N4-[1-(Cyclopropylsulfonylamino)indan-6-yl]-N2-[4-(4,5-dihydro-1H-imidazol-2-yl)phenyl]-5-methyl-2,4-pyrimidinediamine;V-7:(+/−)-N4-[1-(Cyclopropylsulfonylamino)indan-6-yl]-N2-(3,5-dimethyl-4-methoxyphenyl)-5-methyl-2,4-pyrimidinediamine;V-8:(+/−)-N4-[1-(Cyclopropylsulfonylamino)indan-6-yl]-N2-(3,5-dichloro-4-methoxyphenyl)-5-methyl-2,4-pyrimidinediamine;V-9:(1R)-5-Methyl-N4-[(1-(methylsulfonylamino)indan-6-yl]-N2-(3,4,5-trimethoxyphenyl)-2,4-pyrimidinediamine;V-10:(1R)-N2-(3,5-dimethyl-4-methoxyphenyl)-5-methyl-N4-[(1-(methylsulfonylamino)indan-6-yl]-2,4-pyrimidinediamine;V-11:(1R)-5-Methyl-N2-[4-(1-methyl-4-piperidinyl)pheny]-N4-[1-(methylsulfonyl)aminoindan-6-yl]-2,4-pyrimidinediamine;V-12:(1R)-5-Methyl-N4-[1-(methylsulfonyl)aminoindan-6-yl]-N2-[4-(3-pyridinyl)phenyl]-2,4-pyrimidinediamine;V-13:(1R)-N2-(3,5-Dichloro-4-methoxyphenyl))-5-methyl-N4-[1-(methylsulfonyl)aminoindan-6-yl]-2,4-pyrimidinediamine;V-14:(1R)-5-Methyl-N2-[4-(4-methyl-1-piperazinyl)phenyl]-N4-[1-(methylsulfonyl)aminoindan-6-yl]-2,4-pyrimidinediamine;VI-1:5-Chloro-N2-[4-(4-methyl-1-piperazinyl)phenyl]-N4-[1,2,3,4-tetrahydro-2-(ethylsulfonyl)-5-isoquinolinyl]-2,4-pyrimidinediamine;VI-2:5-Chloro-N2-[3-methyl-4-(methyl-1-piperazinyl)phenyl]-N4-[1,2,3,4-tetrahydro-2-(ethylsulfonyl)-5-isoquinolinyl]-2,4-pyrimidinediamine;VI-3:5-Chloro-N2-[6-(4-methyl-1-piperazinyl)-3-pyridinyl]-N4-[1,2,3,4-tetrahydro-2-(ethylsulfonyl)-5-isoquinolinyl]-2,4-pyrimidinediamine;VI-4:5-Chloro-N2-(3,5-dimethyl-4-methoxyphenyl)N4-[1,2,3,4-tetrahydro-2-(ethylsulfonyl)-5-isoquinolinyl]-2,4-pyrimidinediamine;VI-5:5-Chloro-N4-[1,2,3,4-tetrahydro-2-(ethylsulfonyl)-5-isoquinolinyl]-N2-(3,4,5-trimethoxyphenyl)-2,4-pyrimidinediamine;VII-1:5-Chloro-N4-[3,4-dihydro-1,1-dioxide-2H-1,2-benzothiazin-7-yl]-N2-[3,5-dimethyl-4-methoxyphenyl]-2,4-pyrimidinediamine;VII-2:5-Chloro-N4-[3,4-dihydro-1,1-dioxide-2H-1,2-benzothiazin-7-yl]-N2-[4-(N-methylpiperizin-4-yl)phenyl]-2,4-pyrimidinediamine;VII-3:5-Chloro-N4-[3,4-dihydro-1,1-dioxide-2H-1,2-benzothiazin-7-yl]-N2-[4-(N-methylpiperizin-4-yl)pyridine-3-yl]-2,4-pyrimidinediamine;VII-4:5-Chloro-N4-[3,4-dihydro-1,1-dioxide-2H-1,2-benzothiazin-7-yl]-N2-[5-methyl-4-(N-methylpiperizin-4-yl)pyridine-3-yl]-2,4-pyrimidinediamine;VII-5:5-Chloro-N4-[3,4-dihydro-1,1-dioxide-2H-1,2-benzothiazin-7-yl]-N2-[4-(N-methylpiperizin-4-yl)phenyl]-2,4-pyrimidinediamine;VII-6:5-Methyl-N4-[3,4-dihydro-1,1-dioxide-2H-1,2-benzothiazin-7-yl]-N2-[5-methyl-4-(N-methylpiperizin-4-yl)pyridine-3-yl]-2,4-pyrimidinediamine;VII-7:5-Methyl-N4-[3,4-dihydro-1,1-dioxide-2H-1,2-benzothiazin-7-yl]-N2-[5-methyl-4-(N-methylpiperizin-4-yl)pyridine-3-yl]-2,4-pyrimidinediamine;VII-8:5-Methyl-N4-[3,4-dihydro-1,1-dioxide-2H-1,2-benzothiazin-7-yl]-N2-[3,4,5-trimethylphenyl]-2,4-pyrimidinediamine;VII-9:5-Chloro-N4-[3,4-dihydro-1,1-dioxide-2H-1,2-benzothiazin-7-yl]-N2-[3,4,5-trimethylphenyl]-2,4-pyrimidinediamine;VII-10:5-Methyl-N4-[3,4-dihydro-1,1-dioxide-2H-1,2-benzothiazin-7-yl]-N2-[3,5-dimethyl-4-methoxyphenyl]-2,4-pyrimidinediamine;VIII-1: N4,N6-Di(3-aminosulfonylphenyl)-5-methyl-N2-(2,2,4-trimethyl-3-oxo-2H-benz[1,4]oxazin-6-yl)-2,4,6-pyrimidinetriamine;VIII-2:N2-cyclopentyl-N4-(4-cyclopropylsulfonylaminomethyl)phenyl-5-fluoro-2,4-pyrimidinediamine;VIII-3:(+/−)-N2-(1,2-Dimethylbenzimidazol-5-yl)-N4-[1-(methylsulfonylamino)indan-6-yl]-5-methyl-2,4-pyrimidinediamine;VIII-4:5-Fluoro-N4-[(1-methylsulfonyl)indolin-5-yl]-N2-(2-trifluoromethylbenzimidazol-5-yl)-2,4-pyrimidinediamine;VIII-5:(N-4-[(1-methylsulfonyl)indolin-5-yl]-5-fluoro-N2-[3-methyl-4-(4-methylpiperazin-1-yl)phenyl]-2,4-pyrimidinediamine;VIII-6:5-Fluoro-N4-[(1-methylsulfonyl)indolin-5-yl]-N2-(2-methylbenzimidazol-5-yl)-2,4-pyrimidinediamine;VIII-7:N4-[(N-cyclopropylsulfonyl)-1,2,3,4-tetrahydroisoquinolin-6-yl]-N2-(3,5-dimethyl)phenyl-5-methyl-2,4-pyrimidinediamine;VIII-8:5-Amino-N4-(3-aminosulfonylphenyl)-N2-(indazoline-6-yl)-2,4-pyrimidinediamine;VIII-9:N4-[(N-cyclopropylsulfonyl)-1,2,3,4-tetrahydroisoquinolin-6-yl]-N2-(3,5-dimethyl-4-methoxy)phenyl-5-methyl-2,4-pyrimidinediamine;VIII-10:N4-[(N-ethylsulfonyl)-1,2,3,4-tetrahydroisoquinolin-6-yl]-N2-(3,5-dimethyl-4-methoxy)phenyl-5-fluoro-2,4-pyrimidinediamine;VIII-11:5-Methyl-N4-[4-(N-cyclopropylsulfonylamino)methylphenyl]-N2-[5-cyclopropylpyrazol-3-yl)-2,4-pyrimidinediamine;and VIII-12:5-Chloro-N4-[4-(N-cyclopropylsulfonylamino)methylphenyl]-N2-[5-cyclopropylpyrazol-3-yl)-2,4-pyrimidinediamine.20. The method of claim 1, wherein the cell is contacted in vitro.
 21. Amethod of treating allograft transplant rejection in a transplantrecipient, comprising administering to the transplant recipient anamount of a compound effective to treat the allograft transplantrejection wherein the compound is according to claim
 1. 22. Apharmaceutical formulation comprising a compound according to claim 1.